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CN101903378A - Aminotriazole derivatives - Google Patents

Aminotriazole derivatives Download PDF

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CN101903378A
CN101903378A CN200880122188XA CN200880122188A CN101903378A CN 101903378 A CN101903378 A CN 101903378A CN 200880122188X A CN200880122188X A CN 200880122188XA CN 200880122188 A CN200880122188 A CN 200880122188A CN 101903378 A CN101903378 A CN 101903378A
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triazole
ethanoyl
oxazoles
phenyl
ylmethyl
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CN101903378B (en
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丹尼尔·布尔
奥利维尔·考米波夫
塞尔文·库恩
科琳娜·格里索斯托米
泽维尔·莱罗尔
西尔维娅·里卡德-比尔德斯滕
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Aidu West Pharmaceutical Co. Ltd.
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Actelion Pharmaceuticals Ltd
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Abstract

The invention relates to aminotriazole derivatives of formula (I), wherein A, E, R1 and R2 are as defined in the description, their preparation and their use as pharmaceutically active compounds. The compounds are useful for the prevention or treatment of diseases, which respond to the modulation of the ALX receptor such as inflammatory diseases.

Description

Aminotriazole derivatives
Technical field
The present invention relates to the purposes of the novel aminotriazole derivatives and the conduct medicine thereof of formula (I).The present invention also relate to comprise the method that is used to prepare this compound, the pharmaceutical composition that contains one or more formula (I) compound and especially its as the related fields of the purposes of ALX receptor stimulant.
Background technology
ALXR (another name lipoxin (Lipoxin) A4 acceptor, FPRL1; Be disclosed among the WO2003/082314 as nucleotide sequence SEQ ID NO:1) be the member of G protein-coupled receptor family.Found the formyl radical-MET-Bai amine acyl group-phenylpropylamine acid peptide-mediated calcium mobilization of ALXR in response to high density.In addition, find lipid metabolism thing lipoxin A 4 (LXA4) and analogue thereof in the ALXR cells transfected with high-affinity in conjunction with ALXR and increase that arachidonic acid produces and the G protein activation (people such as Chiang, Pharmacol.Rev., 2006,58,463-487).The effect of assessment LXA4 in various animal disease models; And proof LXA4 has effective anti-inflammatory and short (pro-resolution) activity that disappears.LXA4 or derivative or stable analogs show that the disease model of activity in vivo vivid is (for example) skin inflammation, back of the body air bag, local asphyxia/reperfusion injury, peritonitis, colitis, mesangial proliferative nephritis, pleuritis, asthma, cystic fibrosis, sepsis, corneal injury, vasculogenesis, periodontitis, the hyperpathia of carrageenin inductive and graft versus host disease (GvHD) (Serhan and Chiang, Br.J.Pharmacol., 2007,1-16).ALXR is also through differentiating the functional receptor for the peptide of various numbers, this peptide comprise prion protein fragment, be derived from human immunodeficiency virus (HIV)-1 LAIThe peptide of the gp120 of bacterial strain and kind of starch-β 1-42 (Ab42) is (about summary, referring to people such as Le, Protein Pept Lett., 2007,14,846-853), and shown that AL XR participates in (AD) pathogenesis of Alzheimers (Alzheimer ' s Disease) (people such as Yazawa, FASEB J., 2001 with several critical paths, 15,2454-2462).The activation of ALXR causes the protein mediated signal transduction cascade of G on scavenger cell and the microgliacyte, and this increases committed cell migration, phagolysis and amboceptor and discharges.Near the raising senile plaque of the soluble monocyte of these incidents in the affected areas of excessive generation Ab42 and generation cumulative AD brain.Although can think that white cell is intended to remove the congenital host response of toxic agents being accumulated as of tissue injury position, activated mononuclear phagocyte also discharges and variously may have toxic material (for example superoxide anion) to neurone.Therefore, ALXR can mediate by what Ab42 was caused in the AD brain and inspire scorching reaction and make the progression of disease aggravation.Also report Humanin (HN) (a kind of peptide) and the human ALXR of the Ab42 unity of possession in mononuclear phagocyte and the neuronal cell strain with neuroprotective ability; and the neuroprotective activity that has shown HN is attributable to its competitiveness to ALXR and occupies (people such as Ying; J.Immunol.; 2004; 172,7078-7085).
Adjusting, the cytohormone that the biological nature of ALXR agonist includes, but is not limited to adjusting, the inflammation of monocyte/macrophage/microgliacyte migration/activation, neutrophils migration/activation, lymphocyte activation, hyperplasia and differentiation produces and/or the adjusting that discharges, inspire the adjusting that scorching amboceptor produces and/or discharge, the adjusting of immunne response.
Summary of the invention
The invention provides aminotriazole derivatives, it is the non-peptide agonists of human ALX acceptor.This compound is applicable to the disease that prevention or treatment react to the adjusting of ALX acceptor, for example the illness (especially Alzheimer) of the disease of the retroviral infection of inflammatory disease, obstructive airway disease, supersensitivity symptom, HIV mediation, cardiovascular disorder, neural inflammation, nervous disorders, pain, Protein virus mediation and kind of starch mediation; In addition, it is applicable to prevention or treats autoimmune disorders and be applicable to and regulate immunne response (especially those immunne responses that caused by vaccine inoculation).
Hereinafter present various embodiment of the present invention:
1) the present invention relates to the aminotriazole derivatives of formula (I):
Wherein:
A represents phenyl or heterocyclic radical, and wherein two substituting groups are 1, and 3-arranges; Or A represents propane-1,3-two bases;
E represents *-(C 1-C 4) alkyl-O-,-CH=CH-or
Figure BPA00001161879200032
Wherein asterisk is indicated and R 1The key of binding;
Q represents O or S;
R 3Expression hydrogen, (C 1-C 4) alkyl, cyclopropyl, (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl, benzyl or-CH 2CH 2C (O) OtBu;
R 1Expression pyridyl or aryl, this group be unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl; And
R 2Expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) alkyl.
According to embodiment 1) formula (I) compound can contain one or more three-dimensional formation or asymmetric center, for example one or more unsymmetrical carbon.Unless otherwise instructed, otherwise the substituting group at two keys place can (Z) or (E) configuration exist.Therefore, the form of mixtures that formula (I) compound can steric isomer or preferably exist with the pure stereoisomers form.Can come the mixture of separation of stereoisomers in the manner known to persons skilled in the art.Represent at E-situation of CH=CH-under, this pair key can (Z) or (E) configuration exist, preferably it exists with (E) configuration.
Following paragraph provides the definition about the various chemical parts of compound of the present invention, unless and the definition of clearly setting forth in addition wideer or narrower definition is provided, otherwise above-mentioned definition is intended to as one man be applied in whole specification sheets and the claim.
The term that is used alone or in combination " alkyl " refers to contain a straight or branched alkyl to four carbon atom.Term " (C x-C y) " (x and y respectively do for oneself integer) refers to as defined above and contain the alkyl of x to y carbon atom to alkyl.For example, (C 1-C 4) alkyl contains one to four carbon atom.The representative example of alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl and the tertiary butyl.Be preferably (C 1-C 3) alkyl, for example methyl, ethyl, n-propyl and sec.-propyl.(C more preferably 1-C 3) alkyl, for example methyl and ethyl.Most preferably be methyl.
As expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) R of alkyl 2In used (C 1-C 3) example of alkyl is methyl.
As the expression *-(C 1-C 4) used bridge joint (C among the E of alkyl-O- 1-C 4) in the alkyl, Sauerstoffatom and residue R 1Preferably be connected to bridge joint (C 1-C 4) the same carbon atom of alkyl.This bridge joint (C 1-C 4) example of alkyl is methylene radical.
The term that is used alone or in combination " alkoxyl group " refers to alkyl-O-group, and wherein alkyl as defined above.Term " (C x-C y) " (x and y respectively do for oneself integer) refers to as defined above and contain the alkoxyl group of x to y carbon atom to alkoxyl group.For example, (C 1-C 4) alkoxyl group contains one to four carbon atom.The representative example of alkoxyl group comprises methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert.-butoxy.Be preferably oxyethyl group and methoxyl group.Most preferably be methoxyl group.
Term " fluoroalkyl " refers to as defined above and contains the alkyl of one to four (being preferably one to three) carbon atom, wherein one or more (and maying all) hydrogen atom fluorine displacement.Term " (C x-C y) " (x and y respectively do for oneself integer) refers to as defined above and contain the fluoroalkyl of x to y carbon atom to fluoroalkyl.For example, (C 1-C 3) fluoroalkyl contains one to three carbon atom, wherein one to seven hydrogen atom fluorine displacement.The representative example of fluoroalkyl comprises trifluoromethyl and 2,2, the 2-trifluoroethyl.Be preferably (C 1) fluoroalkyl, for example trifluoromethyl and difluoromethyl.Most preferably be trifluoromethyl.
Term " Fluoroalkyloxy " refers to as defined above and contains the alkoxyl group of one to four (being preferably one to three) carbon atom, wherein one or more (and maying all) hydrogen atom fluorine displacement.Term " (C x-C y) " (x and y respectively do for oneself integer) refers to as defined above and contain the Fluoroalkyloxy of x to y carbon atom to Fluoroalkyloxy.For example, (C 1-C 3) Fluoroalkyloxy contains one to three carbon atom, wherein one to seven hydrogen atom fluorine displacement.The representative example of Fluoroalkyloxy comprises trifluoromethoxy, difluoro-methoxy and 2,2,2-trifluoro ethoxy.Be preferably (C 1) Fluoroalkyloxy, for example trifluoromethoxy and difluoro-methoxy.Most preferably be trifluoromethoxy.
Term " hydroxyl-(C 1-C 2) alkyl " refer to as defined above and contain the alkyl of one or two carbon atom, replace by one of them hydrogen atom hydroxyl.Hydroxyl-(C 1-C 2) example of alkyl is hydroxyl-methyl and hydroxyl-ethyl.Be preferably hydroxyl-methyl and 2-hydroxyl-ethyl.
Term " (C 1-C 4) alkoxyl group-(C 1-C 2) " refer to as defined above and contain the alkyl of one or two carbon atom, one of them hydrogen atom is as defined above (C for alkyl 1-C 4) the alkoxyl group displacement.(C 1-C 4) alkoxyl group-(C 1-C 2) representative example of alkyl comprises methoxyl group-methyl, methoxyl group-ethyl (especially 2-methoxyl group-ethyl), oxyethyl group-methyl, oxyethyl group-ethyl (especially 2-oxyethyl group-ethyl), isopropoxy-methyl and isopropoxy-ethyl (especially 2-isopropoxy-ethyl); And be preferably methoxyl group-methyl, methoxyl group-ethyl (especially 2-methoxyl group-ethyl), oxyethyl group-methyl and oxyethyl group-ethyl (especially 2-oxyethyl group-ethyl).
As R 1In used (C 1-C 4) alkoxyl group-(C 1-C 2) preferred embodiment of alkyl is methoxyl group-methyl, methoxyl group-ethyl (especially 2-methoxyl group-ethyl), oxyethyl group-methyl, oxyethyl group-ethyl (especially 2-oxyethyl group-ethyl), isopropoxy-methyl and isopropoxy-ethyl (especially 2-isopropoxy-ethyl).Most preferably be methoxyl group-methyl and methoxyl group-ethyl (especially 2-methoxyl group-ethyl).
As R 3In used (C 1-C 4) alkoxyl group-(C 1-C 2) preferred embodiment of alkyl is methoxyl group-methyl and methoxyl group-ethyl (especially 2-methoxyl group-ethyl).Most preferably be methoxyl group-methyl.
Term " two-[(C 1-C 3) alkyl]-amino " finger through two (C as defined above 1-C 3) amino that replaces of alkyl, wherein these two (C 1-C 3) alkyl can be identical or different.Two-[(C 1-C 3) alkyl]-amino representative example includes, but is not limited to dimethylamino, methyl-ethyl-amino and diethylin.Be preferably dimethylamino.
Term halogen is represented fluorine, chlorine, bromine or iodine, is preferably fluorine, chlorine or bromine and most preferably is fluorine or chlorine.
Phenyl (preferably) or naphthyl represented in the term of form " aryl " alone or in combination.This aryl is unsubstituted, through single replacement, through two replace or through three replace (be preferably and be unsubstituted, replace or through two replacements through single, and most preferably be unsubstituted or through single replacement), wherein substituting group is independently selected from: halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl, and be preferably and be selected from halogen, (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl and (C 1-C 4) Fluoroalkyloxy.Example is phenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-chloro-4-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, 3,5-3,5-dimethylphenyl, 3-p-methoxy-phenyl, 4-p-methoxy-phenyl, 3-methoxyl group-4-aminomethyl phenyl, 3-methoxymethyl-phenyl, 3-methoxy ethyl-phenyl, 3-dimethylamino-phenyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl, 4-trifluoromethyl and 3-Trifluoromethoxyphen-l.Other example is 3-isopropoxy methyl-phenyl and 3-(2-isopropoxy-ethyl)-phenyl.Preferred embodiment is phenyl, 3-p-methoxy-phenyl and 4-trifluoromethyl.
The term of form " heterocyclic radical " expression alone or in combination contains 1,2 or 3 heteroatomic 5 or 6 yuan of monocyclic aromatic rings that are independently selected from oxygen, nitrogen and sulphur.The example of this heterocyclic radical is furyl, oxazolyl, isoxazolyl, oxadiazole base, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyrryl, imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl.Preferred embodiment is furyl (especially furans-2,5-two bases), thienyl (especially thiophene-2,4-two bases and thiophene-2,5-two bases), thiazolyl (especially thiazole-2,4-two bases) and pyridyl (especially pyridine-2,4-two bases and pyridine-2,6-two bases).Another preferred embodiment Wei oxazolyl (You Qi oxazole-2,4-two Ji be Ji oxazole-2,5-two bases).More preferably example is a furans-2,5-two Ji, oxazoles-2,4-two Ji, oxazoles-2,5-two bases, thiophene-2,5-two bases and thiazole-2,4-two bases.Most preferably example is a furans-2,5-two bases and thiophene-2,5-two base and especially be furans-2,5-two bases.
" 1,3-arranges, and " expression is connected to triazole-methyl moiety and residue R respectively as term used in the explanation to " A " 2Phenyl or two atoms of heterocyclic radical separated by an atom each other; For example if " A " represents phenyl, then substituent arrangement is as shown below:
Figure BPA00001161879200091
In this patent application, the tie point of group shown in the dash lines show.For example, group shown below is 2-methyl-oxazoles-4,5-two bases:
Figure BPA00001161879200092
2) another embodiment of the present invention relates to according to embodiment 1) aminotriazole derivatives, wherein:
A represents phenyl or heterocyclic radical, and wherein two substituting groups are 1, and 3-arranges; Or A represents propane-1,3-two bases;
E represents *-CH 2-O-,-CH=CH-or
Figure BPA00001161879200093
Wherein asterisk is indicated and R 1The key of binding;
Q represents O or S;
R 3Expression hydrogen, (C 1-C 4) alkyl, cyclopropyl or (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl;
R 1The expression aryl, this group is unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl; And
R 2Expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) alkyl.
3) another embodiment of the present invention relates to according to embodiment 1) aminotriazole derivatives, wherein:
A represents phenyl or heterocyclic radical, and wherein two substituting groups are 1, and 3-arranges; Or A represents propane-1,3-two bases;
E represents *-(C 1-C 4) alkyl-O-,-CH=CH-or
Figure BPA00001161879200101
Wherein asterisk is indicated and R 1The key of binding;
Q represents O or S;
R 3Expression hydrogen, (C 1-C 4) alkyl or cyclopropyl;
R 1The expression aryl, this group is unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl; And
R 2Expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) alkyl.
4) another embodiment of the present invention relates to according to embodiment 1) or 2) in any aminotriazole derivatives, wherein:
A represents phenyl-1,3-two bases, furans-2,5-two Ji, oxazoles-2,4-two Ji, oxazoles-2,5-two bases, thiophene-2,4-two bases, thiophene-2,5-two bases, thiazole-2,4-two bases, thiazole-2,5-two bases, pyridine-2,4-two bases, pyridine-2,6-two bases or propane-1,3-two bases;
E represents *-CH 2-O-,-CH=CH-or
Figure BPA00001161879200111
Wherein asterisk is indicated and R 1The key of binding;
R 3Expression hydrogen, (C 1-C 4) alkyl, cyclopropyl or (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl;
R 1The expression aryl, this group is unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl; And
R 2Expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) alkyl.
5) another embodiment of the present invention relates to according to embodiment 1) to 4) in any aminotriazole derivatives, wherein exist in the following feature at least one, be preferably all:
A represents phenyl-1,3-two bases, furans-2,5-two bases, thiophene-2,4-two bases, thiophene-2,5-two bases, thiazole-2,4-two bases, pyridine-2,4-two bases, pyridine-2,6-two bases or propane-1,3-two bases;
E represents *-CH 2-O-,-CH=CH-or
Figure BPA00001161879200121
Wherein asterisk is indicated and R 1The key of binding;
R 3Expression hydrogen, (C 1-C 4) alkyl or cyclopropyl;
R 1The expression aryl, this group is unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl; And
R 2Expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) alkyl.
6) another embodiment of the present invention relates to according to embodiment 1) to 4) in any aminotriazole derivatives, wherein:
A represents furans-2,5-two Ji, oxazoles-2,4-two Ji, oxazoles-2,5-two bases, thiophene-2,5-two bases or thiazole-2,4-two bases;
E represents *-CH 2-O-,-CH=CH-or
Figure BPA00001161879200131
Wherein asterisk is indicated and R 1The key of binding;
R 3Expression hydrogen, methyl, ethyl or cyclopropyl;
R 1The expression phenyl, this group is unsubstituted, replace or through two replacements, wherein substituting group is independently selected from: halogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino through single; And
R 2Expression-CO-CH 3
7) another embodiment of the present invention relates to according to embodiment 1) to 6) in any aminotriazole derivatives, wherein exist in the following feature at least one, be preferably all:
A represents furans-2,5-two bases or thiophene-2,5-two bases (especially furans-2,5-two bases);
E represents
Figure BPA00001161879200132
Wherein asterisk is indicated and R 1The key of binding;
R 3Expression hydrogen or methyl;
R 1The expression phenyl, this group is unsubstituted, replace or through two replacements, wherein substituting group is independently selected from: halogen, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino through single; And
R 2Expression-CO-CH 3
8) another embodiment of the present invention also relates to for following formula (I P) formula (I) compound of compound:
Figure BPA00001161879200141
Wherein:
E represents *-(C 1-C 4) alkyl-O-,-CH=CH-or
Figure BPA00001161879200142
Wherein asterisk is indicated and R 1The key of binding;
R 3Expression hydrogen or (C 1-C 4) alkyl;
R 1The expression aryl, it is unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl and (C 1-C 4) Fluoroalkyloxy; And
R 2Expression-CO-(C 1-C 3) alkyl.
9) another embodiment of the present invention relates to according to embodiment 1) to 3) in any aminotriazole derivatives, wherein:
A represents heterocyclic radical, and wherein two substituting groups are 1, and 3-arranges.
10) another embodiment of the present invention relates to according to embodiment 1) to 4) in any aminotriazole derivatives, wherein:
A represents phenyl-1,3-two bases, furans-2,5-two Ji, oxazoles-2,4-two Ji, oxazoles-2,5-two bases (R especially wherein 2Be connected 2), thiophene-2,4-two bases, thiophene-2,5-two bases, thiazole-2,4-two bases (R especially wherein 2Be connected 4), thiazole-2,5-two bases, pyridine-2,4-two bases, pyridine-2,6-two bases or propane-1,3-two bases.
11) another embodiment of the present invention relates to according to embodiment 1) to 5) or 10) in any aminotriazole derivatives, wherein:
A represents phenyl-1,3-two bases, furans-2,5-two bases, thiophene-2,4-two bases (R wherein 2Be connected 2), thiophene-2,5-two bases, thiazole-2,4-two bases (R wherein 2Be connected 4), pyridine-2,4-two bases, pyridine-2,6-two bases or propane-1,3-two bases.
12) another embodiment of the present invention relates to according to embodiment 1) to 4), 6), 9) or 10) in any aminotriazole derivatives, wherein:
A represents furans-2,5-two bases, R 2Be connected 2 Wei De oxazoles-2,4-two bases, R 2Be connected 4 Wei De oxazoles-2,4-two bases, R 2Be connected 2 Wei De oxazoles-2,5-two bases, thiophene-2,5-two bases or R 2Be connected 4 thiazole-2,4-two bases.
13) another embodiment of the present invention relates to according to embodiment 1) to 7) or 9) to 12) in any aminotriazole derivatives, wherein:
A represents furans-2,5-two bases or thiophene-2,5-two bases.
14) another embodiment of the present invention relates to according to embodiment 1) to 6) or 9) to 12) in any aminotriazole derivatives, wherein:
A represents thiazole-2,4-two bases (R wherein 2Be connected 4).
15) another embodiment of the present invention relates to according to embodiment 1) to 7) or 9) to 13) in any aminotriazole derivatives, wherein:
A represents thiophene-2,5-two bases.
16) another embodiment of the present invention relates to according to embodiment 1) to 7) or 9) to 13) in any aminotriazole derivatives, wherein:
A represents furans-2,5-two bases.
17) another embodiment of the present invention relates to according to embodiment 1) to 4), 6), 9), 10) or 12) in any aminotriazole derivatives, wherein:
A represents R 2Be connected 2 Wei De oxazoles-2,4-two bases or R 2Be connected 4 Wei De oxazoles-2,4-two bases.
18) another embodiment of the present invention relates to according to embodiment 1) to 4), 6), 9), 10) or 12) in any aminotriazole derivatives, wherein:
A represents R 2Be connected 2 Wei De oxazoles-2,4-two bases.
19) another embodiment of the present invention relates to according to embodiment 1) to 4), 6), 9), 10) or 12) in any aminotriazole derivatives, wherein:
A represents R 2Be connected 4 Wei De oxazoles-2,4-two bases.
20) another embodiment of the present invention relates to according to embodiment 1) to 4), 6), 9) or 10) in any aminotriazole derivatives, wherein:
A represents R 2Be connected 2 Wei De oxazoles-2,5-two bases or R 2Be connected 5 Wei De oxazoles-2,5-two bases.
21) another embodiment of the present invention relates to according to embodiment 1) to 4), 6), 9), 10) or 12) in any aminotriazole derivatives, wherein:
A represents R 2Be connected 2 Wei De oxazoles-2,5-two bases.
22) another embodiment of the present invention relates to according to embodiment 1) to 5), 10) or 11) in any aminotriazole derivatives, wherein:
A represents phenyl-1,3-two bases.
23) another embodiment of the present invention relates to according to embodiment 1) to 5), 10) or 11) in any aminotriazole derivatives, wherein:
A represents propane-1,3-two bases.
24) another embodiment of the present invention relates to according to embodiment 1) to 6) or 8) to 23) in any aminotriazole derivatives, wherein:
E represents *-(C 1-C 4) alkyl-O-(is preferably *-CH 2-O-) or-CH=CH-,
Wherein asterisk is indicated and R 1The key of binding.
25) another embodiment of the present invention relates to according to embodiment 1) to 6) or 8) to 24) in any aminotriazole derivatives, wherein:
E represents *-(C 1-C 4) alkyl-O-(is preferably *-CH 2-O-),
Wherein asterisk is indicated and R 1The key of binding;
26) another embodiment of the present invention relates to according to embodiment 1) to 6) or 8) to 24) in any aminotriazole derivatives, wherein:
E represents-CH=CH-.
27) another embodiment of the present invention relates to according to embodiment 1) to 23) in any aminotriazole derivatives, wherein E represents:
Figure BPA00001161879200181
Wherein asterisk is indicated and R 1The key of binding;
28) another embodiment of the present invention relates to according to embodiment 1), 2), 4), 9) to 23) or 27) in any aminotriazole derivatives, wherein:
R 3Expression hydrogen, (C 1-C 4) alkyl, cyclopropyl, methoxyl group-methyl or 2-methoxyl group-ethyl.
29) another embodiment of the present invention relates to according to embodiment 1) to 23) or 27) in any aminotriazole derivatives, wherein:
R 3Expression hydrogen or methyl.
30) another embodiment of the present invention relates to according to embodiment 1) to 3) or 9) to 23) in any aminotriazole derivatives, wherein:
Q represents O.
31) another embodiment of the present invention relates to according to embodiment 1) to 5) or 9) to 30) in any aminotriazole derivatives, wherein:
R 1The expression phenyl, it is unsubstituted, replace or through two replacements, wherein substituting group is independently selected from: halogen, (C through single 1-C 4) alkyl (especially methyl), (C 1-C 4) alkoxyl group (especially methoxyl group), trifluoromethyl, trifluoromethoxy and dimethylamino.
32) another embodiment of the present invention relates to according to embodiment 1) to 31) in any aminotriazole derivatives, R wherein 1Expression is unsubstituted or through mono-substituted phenyl, wherein substituting group is selected from: halogen, (C 1-C 4) alkoxyl group (especially methoxyl group) and trifluoromethyl.
33) another embodiment of the present invention relates to according to embodiment 1) or 9) to 30) and in any aminotriazole derivatives, wherein:
R 1The expression pyridyl, it is unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl.
34) another embodiment of the present invention relates to according to embodiment 1) or 9) to 30) and in any aminotriazole derivatives, wherein:
R 1The expression pyridyl, it is through (C 1-C 4) the single replacement of fluoroalkyl (especially trifluoromethyl).
35) another embodiment of the present invention relates to according to embodiment 1) to 5) or 9) to 34) in any aminotriazole derivatives, R wherein 2Expression-CO-(C 1-C 3) alkyl (especially-CO-CH 3) or-CF 2-(C 1-C 3) alkyl (especially-CF 2-CH 3).
36) another embodiment of the present invention relates to according to embodiment 1) to 5) or 9) to 35) in any aminotriazole derivatives, R wherein 2Expression-CF 2-(C 1-C 3) alkyl (especially-CF 2-CH 3).
37) another embodiment of the present invention relates to according to embodiment 1) to 35) in any aminotriazole derivatives, R wherein 2Expression-CO-(C 1-C 3) alkyl (especially-CO-CH 3).
38) as enforcement mode 1) defined preferred formula (I) compound is selected from:
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide);
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
Two keys of listed acrylamide derivative can be (E) or (Z) configuration (be preferably and be (E) configuration) in enumerating wherein.
39) as enforcement mode 1) defined other preferred formula (I) compound is selected from:
5-phenyl-oxazoles-4-formic acid [2-(5-oxygen-hexyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-chloro-phenyl)-acrylamide) (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-chloro-phenyl)-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide (is preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-neighbour-tolyl-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-neighbour-tolyl-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-chloro-4-fluoro-phenyl)-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-chloro-4-fluoro-phenyl)-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-between-tolyl-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-between-tolyl-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-is right-tolyl-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-is right-tolyl-acrylamide);
N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-methoxyl group-phenyl)-acrylamide (be preferably (E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-methoxyl group-phenyl)-acrylamide);
5-(3,5-dimethyl-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-4-methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-neighbour-tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-ethyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-cyclopropyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-phenyl-oxazole-4-formic acid [2-(5,5-two fluoro-hexyls)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(5-methane sulfonyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
[2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(6-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxymethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-thiazole-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-pyridin-4-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(2-ethanoyl-pyridin-4-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiene-3-yl-methyl)-2H-[1,2,3] triazole-4-yl]-acid amides; And
Between 2-methyl-5--tolyl-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Two keys of listed acrylamide derivative can be (E) or (Z) configuration (be preferably and be (E) configuration) in enumerating wherein.
40) as enforcement mode 1) defined other preferred formula (I) compound is selected from:
5-phenyl-oxazoles-4-formic acid [2-(3-ethanoyl-isoxazole-5-base methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-isopropoxy methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
N-[2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
N-[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide;
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-thiazole-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-oxazoles-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methoxymethyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-(2-methoxyl group-ethyl)-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-butyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-sec.-propyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide;
2-benzyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
3-{4-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-base amine formyl]-5-phenyl-oxazoles-2-yl }-the propionic acid tert-butyl ester;
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 5--tolyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(2-ethanoyl-oxazoles-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester; And
5-(6-trifluoromethyl-pyridine-2-yl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Two keys of listed acrylamide derivative can be (E) or (Z) configuration (be preferably and be (E) configuration) in enumerating wherein.
When suitable and convenient, above or hereinafter formula (I) compound any mentioned that part should be understood that also to mention the salt of this formula (I) compound, pharmacy acceptable salt especially.
Term " pharmacy acceptable salt " refers to nontoxicity, inorganic or organic acid and/or base addition salt, and pertinent literature is " Salt selection for basicdrugs " for example, Int.J.Pharm. (1986), 33,201-217.
If will use plural form to compound, salt, pharmaceutical composition, disease and fellow thereof, then this is intended to also represent simplification compound, salt or its fellow.
According to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be suitable for and make medicament.Particularly, formula (I) compound is regulated the ALX acceptor, be that it serves as the ALX receptor stimulant and is applicable to prevention or disease that treatment reacts to the activation of ALX acceptor, the illness (especially Alzheimer) of the disease of the retroviral infection of inflammatory disease, obstructive airway disease, supersensitivity symptom, HIV mediation, cardiovascular disorder, neural inflammation, nervous disorders, pain, Protein virus mediation and kind of starch mediation for example; In addition, it is applicable to and regulates immunne response (especially those immunne responses that caused by vaccine inoculation).Specific, formula (I) compound is applicable to the disease that prevention or treatment are for example following: the disease of inflammatory disease, obstructive airway disease, supersensitivity symptom, cardiovascular disorder, neural inflammation, nervous disorders, pain, Protein virus mediation and the illness (especially Alzheimer) of kind of starch mediation.
In detail, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to that prevention or treatment are selected from the disease of inflammatory disease, obstructive airway disease and supersensitivity symptom.
Inflammatory disease, obstructive airway disease and supersensitivity symptom include, but is not limited among following disease and the illness group one, several or all:
1) acute lung injury (ALI); Grow up/acute respiratory distress syndrome (ARDS); Chronic obstructive lung, tracheae or tuberculosis (COPD, COAD or COLD) comprise chronic bronchitis or relative expiratory dyspnea; Pulmonary emphysema; And by other medicines therapy, especially other inhaled drugs therapy and the over-reactive aggravation of tracheae that causes.Specific, inflammatory disease, obstructive airway disease and supersensitivity symptom comprise COPD, COAD and COLD.
2) other inflammatory disease, obstructive airway disease and supersensitivity symptom comprise the bronchitis of any kind or origin.
3) other inflammatory disease, obstructive airway disease and supersensitivity symptom comprise the bronchiectasis and the Pneumonoconiosis (pneumoconiosis) of any kind or origin.
4) other inflammatory disease, obstructive airway disease and supersensitivity symptom comprise the asthma of any kind or origin, comprise endogenous (nonallergic) asthma and exogenous (supersensitivity) asthma, mild asthma, moderate bronchial asthma, serious asthma, segmental bronchus inflammatory asthma, exercise induced property asthma, occupational asthma and inductive asthma behind infectation of bacteria.
5) in another embodiment, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be particularly useful for the prevention or the treatment inflammatory disease.Inflammatory disease comprise among following disease and the illness group one, several or all:
5a) in detail, inflammatory disease refers to the neutrophils associated conditions, and especially the relevant tracheae illness of neutrophils comprises that excessive Neutrophils increases, and this is because it influences tracheae and/or lung.Other neutrophils associated conditions also comprises periodontitis, glomerule ephritis and cystic fibrosis.
5b) other inflammatory disease comprises dermatosis, for example psoriasis, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, scleroderma, allergic angiitis, Qian Ma rash, lupus erythematosus and epidermolysis.
5c) other inflammatory disease also relates to disease or the symptom with inflammatory component.Have the disease of inflammatory component or disease and the symptom that symptom includes, but is not limited to influence eyes, for example conjunctivitis, drying keratoconjunctivitis and vernal conjunctivitis; Influence the disease of nose, comprise allergic rhinitis; And the inflammatory diseases that involves autoimmune reaction or have autoimmune component or cause of disease, for example systemic lupus erythematosus disease, polychondritis, scleroderma, Wegener (Wegener) granuloma disease, dermatomyositis, chronic active hepatitis, myasthenia gravis, Shi Difen-Jonson's syndromes (Stevens-Johnsonsyndrome), idiopathic steatorrhea, autoimmune inflammatory intestinal tract disease (for example ulcerative colitis and Crohn disease (Crohn ' s disease)), endocrine ophthalmopathy, the chronic anaphylaxis pneumonia, primary biliary cirrhosis, drying keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, arthritic psoriasis and glomerule ephritis.
5d) other inflammatory disease that involves autoimmune reaction or have autoimmune component or a cause of disease comprises rheumatoid arthritis, Hashimoto Tiroidina (hishimoto ' s thyroid) and I type or type ii diabetes.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt retroviral infection of being applicable to prevention or treatment HIV mediation.
The retroviral infection of HIV mediation include, but is not limited to by one among HIV-1 and caused disease of HIV-2 virus strain and the illness group, several or all, this HIV-1 virus strain and this HIV-2 virus strain be GUN-4v, GUN-7wt, AG204, AG206, AG208, HCM305, HCM308, HCM342, mSTD104 and HCM309 for example.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to the prevention or the treatment cardiovascular disorder.
Cardiovascular disorder refers to one or more disease patient's condition of cardiovascular tree (comprising heart) and the disease of dependency organ.The disease patient's condition of cardiovascular tree and the disease of dependency organ include, but is not limited to myocardium illness (myocardosis or myocarditis), for example idiopathic cardiomyopathy, the metabolic cardiomyopathy that comprises diabetic cardiomyopathy, alcoholic cardiomyopathy, drug-induced property myocardosis, ischemic cardiomyopathy and hypertensive cerebral myocardosis; The atheroma disease of important blood vessels (great vessels disease), this important blood vessels for example aorta, coronary artery, carotid artery, cerebrovascular artery, the Renal artery, iliac artery, femoral artery Ji the popliteal artery; Toxic, drug-induced property and metabolic (comprising hypertensive cerebral and/or diabetic) small vessel disease disease (microvascular disease), this little blood vessel be retina arteriole, renal glomerulus arteriole, vasa nervorum, heart arteriole and eyes, kidney, heart and maincenter and peripheral neural associated capillary bed for example; And the plaque rupture of the atheroma pathology of important blood vessels, this important blood vessels is aorta, coronary artery, carotid artery, cerebrovascular artery, the Renal artery, iliac artery, femoral artery and popliteal artery for example.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to prevention or treat neural inflammation.Neural inflammation phalangeal cell signal transducers produces, the activation of neuroglia or neuroglia activated channel and reaction, inspire inflammatory cell hormone or chemotactic hormone, the activation of astroglia cell or astroglia cell activated channel and reaction, the activation of mesoglia or mesoglia activated channel and reaction, the reaction that oxidative pressure is relevant (for example nitric oxide synthase produces and the nitrogen oxide accumulation), acute phase protein, the loss of synaptophysin (synaptophysin) and PDM-95 albumen (PSD-95), the component of complement cascade, the loss of cynapse function or reduction, protein kinase activity (for example dead related protein kinase enzymic activity), behavioral deficiency, cell injury (for example neuronal cell injury), the kind of starch β deposition of necrocytosis (for example neuronal cell death) and/or kind of starch patch.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to the prevention or the treatment nervous disorders.
In detail, nervous disorders includes, but is not limited to epilepsy, apoplexy, cerebral ischemia, middle cerebral artery aneurysm, the recurrent multiple sclerosis, carrying out property multiple sclerosis, A Erposishi disease (Alpers ' disease), amyotrophic lateral sclerosis (ALS), senile dementia, Louis (Lewy) body dementia, the special syndromes (Rhett syndrome) of thunder, spinal cord injuries receptor, traumatic brain injury, trigeminal neuralgia, glossopharyngeal neuralgia, bell's palsy (Bell ' spalsy), myasthenia gravis, muscular dystrophy, progressive muscular atrophy disease, carrying out property oblongata sex-controlled inheritance muscular dystrophy, protrusion of intervertebral disc, break or prolapse syndromes, cervical spondylosis (cervical spondylosis), the illness of clump, thoracic outlet destruction syndrome, the periphery neuropathy, mild cognitive descends, cognitive decline, Alzheimer, Parkinson's disease (Parkinson ' sdisease) and huntington's chorea (Huntington ' s chorea).
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to the prevention or the treatment pain.Pain includes, but is not limited to for example following illustrative neuropathy sex change of symptom pain: pain, myelopathic or nerve root characteristic of disease pain, atypical facial nerve and cusalgia sample syndromes after pain, the amputation after diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, painful diabetes polyneuropathy, the apoplexy.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt disease of being applicable to prevention or treatment Protein virus mediation.The disease that also is called the Protein virus mediation of Transmissible spongiform encephalopathy (TSE) include, but is not limited to Kuru disease (kuru), Ge-Si two syndromes ( Syndrome, GSS), fatal familial insomnia (FFI) and storehouse Jia Shi disease (Creutzfeldt-Jakob Disease, CJD).
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt illness of being applicable to treatment kind of starch mediation.The illness of kind of starch mediation be defined as by kind of starch or kind of starch sample albumen caused or with relevant disease and illness.By kind of starch or kind of starch sample albumen caused or with relevant disease and illness include, but is not limited to Alzheimer (AD), comprise the disease or the symptom of the loss that is characterised in that cognitive memory capacity, for example mild cognitive impairment (MCI); Dementia with Lewy body; Down's syndrome (Down ' s syndrome); Hematencephalon with amyloidosis.In another embodiment, caused by kind of starch or kind of starch sample albumen or with relevant disease and illness comprise paralysis on the carrying out property nuclear, multiple sclerosis, storehouse Jia Shi disease, Parkinson's disease, HIV dependency dementia, amyotrophic lateral sclerosis (ALS), inclusion body myositis (IBM), grow up outbreak diabetes and old cardiac amyloidosis.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to the adjusting immunne response.
The adjusting of immunne response includes, but is not limited to based on use at least a antigen and at least a according to embodiment 1 to the person under inspection) to 40) in any formula (I) compound or the method for compositions of its pharmacy acceptable salt.In some cases, at first use and contain antigenic composition, then use at least a according to embodiment 1) to 40) in any formula (I) compound or the composition of its pharmacy acceptable salt.In other cases, use at last and contain antigenic composition.Can be simultaneously, use different compositions with approaching order or time of separating.Be provided for those method and compositions of therapeutic and preventative immunization (promptly have a mind to excite, strengthen, strengthen or regulate adaptability and/or innate immunity is replied).Specific advantages can comprise one in the following advantage or many persons:
1) compare with administration of antigens only, use at least a according to embodiment 1) to 40) and in any formula (I) compound or its pharmacy acceptable salt and antigen after immunne response quickened;
2) bigger to a small amount of susceptibility of the antigen (for example toxin or pathogenic agent) that strong immunization replys of usually can not inducing; And
3) antitumor therapy is more effective.
In addition, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to prevention or treatment cystic fibrosis, pulmonary fibrosis, pulmonary circulation hyperpiesia, wound healing, diabetic nephropathy, be applicable to the inflammation that reduces transplanted tissue, be applicable to that prevention or treatment are by the caused inflammatory disease of pathogenic organism.
Specific, according to embodiment 1) to 40) in any formula (I) compound or its pharmacy acceptable salt be applicable to that prevention or treatment are selected among following disease and the illness group one, several or whole diseases:
1) inflammatory disease, obstructive airway disease and supersensitivity symptom, for example acute lung injury (ALI); Grow up/acute respiratory distress syndrome (ARDS); And the asthma of any kind or origin, comprise endogenous (nonallergic) asthma and exogenous (supersensitivity) asthma, mild asthma, moderate bronchial asthma, serious asthma, segmental bronchus inflammatory asthma, exercise induced property asthma, occupational asthma and inductive asthma behind infectation of bacteria;
2) inflammatory disease, neutrophils associated conditions for example, especially the relevant tracheae illness of neutrophils comprises that excessive Neutrophils increases (this is because it influences tracheae and/or lung); Periodontitis; Glomerule ephritis; Cystic fibrosis; And dermatosis, for example psoriasis, contact dermatitis, atopic dermatitis, dermatitis herpetiformis, scleroderma, allergic angiitis, Qian Ma rash, lupus erythematosus and epidermolysis;
3) have the disease of inflammatory component, for example influence the disease and the symptom of eyes, for example conjunctivitis, drying keratoconjunctivitis and vernal conjunctivitis; The inflammatory diseases that involves autoimmune reaction or have autoimmune component or cause of disease; And autoimmune inflammatory intestinal tract disease (for example ulcerative colitis and Crohn disease);
4) retroviral infection of HIV mediation, for example by HIV-1 and caused disease of HIV-2 virus strain and illness, this virus strain is GUN-4v, GUN-7wt, AG204, AG206, AG208, HCM305, HCM308, HCM342, mSTD104 and HCM309 for example;
5) neural inflammation, the reaction that the activation of its phalangeal cell signal transducers generation, neuroglia or neuroglia activated channel and reaction, the activation that inspires activation, mesoglia or the mesoglia activated channel and the reaction of inflammatory cell hormone or chemotactic hormone, astroglia cell or astroglia cell activated channel and reaction, oxidative pressure are correlated with (for example kind of starch β of kind of starch patch deposition);
6) nervous disorders, for example apoplexy, cerebral ischemia, Alzheimer and Parkinson's disease;
7) also be called the disease of the Protein virus mediation of Transmissible spongiform encephalopathy (TSE), for example Kuru disease, Ge-Si two syndromes (GSS), fatal familial insomnia (FFI) and storehouse Jia Shi disease (CJD);
8) illness of kind of starch mediation;
9) cystic fibrosis, wound healing and inflammatory disease (being caused) by pathogenic organism.
The present invention also relates to according to embodiment 1) to 40) in any purposes of formula (I) compound, it is used to prepare in order to treatment and/or prevents the pharmaceutical composition of above-mentioned disease.
The present invention also relates to according to embodiment 1) to 40) in any pharmacy acceptable salt and the pharmaceutical composition and preparation of formula (I) compound.
Pharmaceutical composition of the present invention contains at least a according to embodiment 1) to 40) in any formula (I) compound (or its pharmacy acceptable salt) as promoting agent, and randomly contain carrier and/or thinner and/or adjuvant.
According to embodiment 1) to 40) in any formula (I) compound and pharmacy acceptable salt thereof can be used as medicament, (for example) is and is suitable in the intestines or the pharmaceutical compositions of parenteral administration.
Mode that can any those skilled in the art were familiar with (referring to, Remington for example, The Science and Practice of Pharmacy, the 21st edition (2005), the 5th part, " Pharmaceutical Manufacturing " is [by Lippincott Williams ﹠amp; Wilkins publishes]), by make randomly with other treatment go up described formula (I) compound of useful combinations of substances or its pharmacy acceptable salt with suitably, compatible solid or liquid carrier materials and when needing (if) common medical adjuvant form the Galenic formula administration form and realize preparation of drug combination on the nontoxicity, inertia, treatment.
The present invention also relates to a kind of method that is used to prevent or treat mentioned disease of this paper or illness, its comprise to object use the medicine and pharmacology live vol according to embodiment 1) to 40) and in any formula (I) compound or its pharmacy acceptable salt.
Unless use, refer to that in this application deducting 10% of X from X extends to 10% the interval that X adds X otherwise be placed on the preceding term of numerical value " X " " pact ", and preferably finger deducts 5% of X from X and extends to 5% the interval that X adds X about temperature.Under particular case, be placed on the preceding term of temperature " Y " " pact " and refer to that in this application deducting 10 ℃ from temperature Y extends to the interval that Y adds 10 ℃, and refer to that preferably deducting 5 ℃ from Y extends to the interval that Y adds 5 ℃ about temperature.In addition, term " room temperature " (rt) refers to about 25 ℃ temperature as used in this article.
Can be by the method for hereinafter being given, come manufacturing formula (I) compound by the method for being given in the example or by similar approach.Most preferably reaction conditions can change with employed specific reactants or solvent, but this condition can be determined according to the optimization routine program by those skilled in the art.
If not indication in addition, then general group A, E, Q, R 1, R 2And R 3Such as for formula (I) definition.Other used abbreviation of definition in experimental section.As general radicals R used in following structure 4b, 4c and 7 uExpression hydrogen or (C 1-C 3) alkyl.As general radicals R used in following structure 4 and 6 xExpression (C 1-C 2) alkyl or two R xForm ethane-1 together, 2-two Ji Qiao.As general radicals R used in following structure 4 and 6 yExpression (C 1-C 3) alkyl.As general radicals R used in the following route map 4 zExpression (C 1-C 4) alkyl.Represent (C as general carboxyl-protecting group R used in (for example) structure 3 or 5 in the universal program of following route map and experimental section 1-C 4) alkyl, be preferably methyl or ethyl.As general group Si used in following structure 4c and 7 PGRepresent suitable silylation protecting group, for example TMS, TIPS, TBDMS or TBDPS are preferably TBDMS.
Decide on used reaction conditions, alcohol can cause indivedual muriates or indivedual mesylate derivatives to form with the reaction of methane sulfonyl chlorine; Know in this area, the subtle change of this reaction conditions can have influence to the result of this reaction; Should be appreciated that two kinds of reagent of muriate and methanesulfonates in the reaction of the following stated usually applicable do electrophile.
In some cases, general group A, E, Q, R 1, R 2And R 3May be with the illustrated molectron of following route map inconsistent and therefore will need to use protecting group (PG).The purposes of protecting group known by the people in this area (referring to, for example " Protective Groups in Organic Synthesis ", T.W.Greene, P.G.M.Wuts, Wiley-Interscience, 1999).For the purpose of the purpose of this argumentation, will suppose that this protecting group is present on the appropriate location when being necessary.
A. final product is synthetic
Part A .a hereinafter) to A.d) universal method be used for preparation formula (I) compound described.
A.a) can by with suitable chloro-formic ester R 1(E represents *-(C to-E-COCl 1-C 4) alkyl-O-) under the temperature of about room temperature or with formula R 1-E-COCl (E represents to Ding Yi De oxazole or thiazolyl group suc as formula (I) Suo, or-suitable carboxylic acid chloride CH=CH-) under the temperature of about room temperature at for example CH 2Cl 2Appropriate solvent at for example Et 3There is reaction down in the alkali of N or DIPEA, by amine preparation formula (I) compound of structure 1.If can not buy, then can be under the temperature of about room temperature by with carbonyl chloride at for example CH 2Cl 2Appropriate solvent at for example Et 3The alkali of N exists down, and reaction prepares suitable chloro-formic ester by correspondent alcohol.If can not buy, then can under the temperature of about room temperature by preparing suitable carboxylic acid chloride by corresponding carboxylic acid in the appropriate solvent of for example toluene, reacting in the presence of the DMF with the reagent of for example oxalyl chloride.Perhaps, can use the standard amide coupling condition of for example EDC/HOBt/DMAP, TBTU, HBTU or PyBOP at for example DIPEA or Et 3The alkali of N exists to descend under the temperature of about room temperature at for example CH 2Cl 2Appropriate solvent in make the amine and the formula R of structure 1 1The corresponding carboxylic acid coupling of-E-COOH.Represent *-(C at E 1-C 4) under the situation of alkyl-O-, can by (for example) with chloroformic acid 4-nitro phenyl ester in the appropriate solvent of for example AcCN at for example Et 3There is the compound of activation structure 1 down in the alkali of N or DIPEA, perhaps by using (for example) carbonyl chloride at for example CH 2Cl 2Appropriate solvent at for example Et 3The alkali of N or DIPEA exists down by R 1(E represents *-(C to-E-H 1-C 4) alkyl-O-) original position forms chloro-formic ester, makes the amine and the formula R of structure 1 1The correspondent alcohol coupling of-E-H.
Figure BPA00001161879200441
Can pass through at for example Pd/C, Pt/C or PtO 2Metal catalyst exist down in the appropriate solvent of for example MeOH or EtOH, carrying out hydrogenation under the temperature of about room temperature and reduce nitro, or the metal by using iron for example is at for example H 2Reducing under the temperature in room temperature to 95 ℃ scope in the presence of the ammonium chloride in the solvent mixture of O/EtOH, obtaining the compound of structure 1 by the compound of structure 2.
A.b) or, can prepare R by comprising following program 2Expression-CO-(C 1-C 3) formula (I) compound of alkyl:
■ uses for example NaBH under the standard reductive condition 4Reagent in the solvent of for example MeOH under the temperature of about room temperature, the reagent that perhaps uses DiBAL for example is reduced into correspondent alcohol with the ester of structure 3 under-78 ℃ of temperature to the room temperature range approximately in the solvent of for example THF;
■ uses for example MnO under the standard oxidation condition 2, chloro-chromic acid pyrrole ingot or NMO/TPAP reagent at for example AcCN or CH 2Cl 2Solvent under the temperature of about room temperature, alcohol is oxidized to corresponding aldehyde;
■ adds alkyl jesse greener (Grignard) reagent in the solvent of for example THF under the temperature that is lower than room temperature (being preferably about-78 ℃), perhaps under about 0 ℃ temperature at for example CH 2Cl 2Solvent in add trialkylaluminium reagent, obtain corresponding secondary alcohol; And
■ uses for example TPAP/NMO or MnO under the standard oxidation condition 2Reagent at for example CH 2Cl 2Or in the solvent of AcCN under the temperature of about room temperature oxidation alcohol so that the compound of formula (I) to be provided.
A.c) or, can go protection to come preparation formula (I) compound the ketal of structure 4 by using following standard conditions:
■ uses the acid of for example rare HCl aqueous solution under the temperature of about room temperature in the solvent of for example THF; Or
■ uses SCX silica gel in the solvent of for example MeOH; Or
■ uses for example silica gel bonded acid of tosic acid in the solvent of for example MeOH; Or
■ uses for example acid of formic acid under about 0 ℃ of temperature to about 50 ℃ of scopes in the solvent of for example water.
Figure BPA00001161879200461
A.d) or, can prepare R by following program 2Expression-CO-(C 1-C 3) formula (I) compound of alkyl:
■ uses for example TPAP/NMO or MnO under the standard oxidation condition 2Reagent at for example CH 2Cl 2Or in the solvent of AcCN under the temperature of about room temperature oxidation structure 4b (R uExpression (C 1-C 3) alkyl) and alcohol;
Or
■ self-structure 4b (R uExpression hydrogen) alcohol begins to carry out at A.b) oxidation-interpolation-oxidation program described in three steps in back down.
Figure BPA00001161879200462
B. intermediate is synthetic
Can according to as above part A .b) described in program by the compound of structure 5 or according to as above part A .c) described in program by the compound R of structure 6 2Expression-CO-(C 1-C 3) compound of structure 2 of alkyl.Can be by R 2Expression-CO-(C 1-C 3) compound and for example (diethylin) sulphur trifluoride of structure 2 of alkyl or the fluorizating agent of (two (2-methoxy ethyl) amido) sulphur trifluoride prepare R under about 60 ℃ temperature in the solvent of for example toluene 2Expression-CF 2-(C 1-C 3) compound of structure 2 of alkyl.
Can be by making methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters and 4-nitro-2H-[1,2,3] triazole is at for example K 2CO 3Or Cs 2CO 3Alkali exist down in the solvent of for example acetone or AcCN under the temperature of about room temperature or 80 ℃ (adding or not adding under the situation of Tetrabutyl amonium bromide) to react to prepare A Biao Shi oxazole-2, the compound of the structure 2 of 4-two bases.Perhaps, can in the solvent of for example DMF, acetone or both mixtures, react under the temperature about room temperature or 50 ℃ in the presence of the alkali of for example DIPEA.
Can be by making 1-(5-chloromethyl-isoxazole-3-bases)-ethyl ketone and 4-nitro-2H-[1,2,3] triazole is at for example K 2CO 3Or Cs 2CO 3Alkali exist down in the solvent of for example acetone or AcCN under the temperature of about room temperature or 80 ℃ (adding or not adding under the situation of Tetrabutyl amonium bromide) to react to prepare A Biao Shi isoxazole-2, the compound of the structure 2 of 4-two bases.Perhaps, can in the solvent of for example DMF, acetone or both mixtures, react under the temperature about room temperature or 50 ℃ in the presence of the alkali of for example DIPEA.
In more general mode, can be by making Ms-O-CH 2-A-C (O)-(C 1-C 3) alkyl or Cl-CH 2-A-C (O)-(C 1-C 3) alkyl (especially 1-(5-chloromethyl-isoxazole-3-bases)-ethyl ketone or methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters) and 4-nitro-2H-[1,2,3] triazole is at for example K 2CO 3Or Cs 2CO 3Alkali have down in the solvent of for example acetone or AcCN that (adding or not adding under the situation of Tetrabutyl amonium bromide) reacts the compound for preparing structure 2 under the temperature of about room temperature or 80 ℃.Perhaps, can in the solvent of for example DMF, acetone or both mixtures, react under the temperature about room temperature or 50 ℃ in the presence of the alkali of for example DIPEA.
Can be by making 4-nitro-2H-[1,2,3] triazole (people such as T.E.Eagles, Organic preparations and procedures 2 (2), 117-119,1970; P.N.Neuman J.Heterocycl.Chem.8,51-56,1971) at for example K 2CO 3Or Cs 2CO 3Alkali exist down (adding or not adding under the situation of Tetrabutyl amonium bromide) in the solvent of for example acetone or AcCN under the temperature of about room temperature or 80 ℃ with Cl-CH 2-A-SO 2-(C 1-C 3) alkyl (especially 2-chloromethyl-5-methane sulfonyl-furans) reaction prepares R 2Expression-SO 2-(C 1-C 3) compound of structure 2 of alkyl.Perhaps, can in the solvent of for example DMF, acetone or both mixtures, react under the temperature about room temperature or 50 ℃ in the presence of the alkali of for example DIPEA.
Can with part A .a) described in program similar respectively by the compound structure 3 of structure 5 and 6 and 4 compound.
Figure BPA00001161879200481
But the individual compound of self-structure 3 begins to pass through A.b) the following first step (R of described program uRepresent hydrogen) or first three step (R uExpression (C 1-C 3) alkyl) compound of preparation structure 4b.
Perhaps, but the individual compound of self-structure 4c begin, in as the solvent of THF, use TBAF to prepare the compound of structure 4b by the silylation protective reaction.
Can with part A .a) described in the compound of the similar compound structure 4c by following structure 7 of program:
Figure BPA00001161879200492
Can be by making 4-nitro-2H-[1,2,3] triazole (people such as T.E.Eagles, Organic preparations and procedures 2 (2), 117-119,1970; P.N.Neuman J.Heterocycl.Chem.8,51-56,1971) with (for example) commercially available 5-chloromethyl-furans-(A represents furans-2 to the 2-manthanoate, 5-two bases) or commercially available 5-bromo-valerate (A represents propane-1,3-two bases) or 4-chloromethyl-thiazole-2-manthanoate (A represents thiazole-2,4-two bases) reaction prepare the compound of structure 5.If then this reaction can be at for example K suitably, 2CO 3Or Cs 2CO 3Alkali exist down in the solvent of for example acetone or AcCN under the temperature of about room temperature or 80 ℃ and under the situation of interpolation Tetrabutyl amonium bromide, carry out.Perhaps, this reaction can carried out under the temperature about room temperature or 50 ℃ in the solvent of for example DMF, acetone or both mixtures in the presence of the alkali of for example DIPEA.
The compound that can prepare structure 6 like each thing below using: represent furans-2 at A with the compounds of those structures 5, under the situation of 5-two bases, suitable shielded furan derivatives, for example 2-(5-chloromethyl-furans-2-yl)-2-methyl-[1,3] dioxolane; Or represent propane-1 at A, and under the situation of 3-two bases, suitable shielded 4-bromo-butyl ketone derivatives, for example 2-(4-bromo-butyl)-2-methyl-[1,3] dioxolane; Or represent thiophene-2 at A, and under the situation of 5-two bases, suitable shielded thiophene derivant, for example 2-(5-chloromethyl-thiophene-2-yl)-2-methyl-[1,3] dioxolane; Or represent phenyl-1 at A, and under the situation of 3-two bases, suitable shielded phenyl derivatives, for example methanesulfonic 3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl ester; Or represent pyridine-2 at A, and under the situation of 6-two bases, suitable shielded pyridine derivate, for example methanesulfonic 6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters; Or represent pyridine-2 at A, under the situation of 4-two bases, suitable shielded pyridine derivate, for example methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters or methanesulfonic 2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl methyl esters; Or represent thiazole-2 at A, and under the situation of 4-two bases, suitable shielded thiazole derivative, for example methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters or 4-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole; Or represent thiophene-2 at A, and under the situation of 4-two bases, suitable shielded thiophene derivant, for example 2-(4-chloromethyl-thiophene-2-yl)-2-methyl-[1,3] dioxolane or 2-(5-chloromethyl-thiene-3-yl-)-2-methyl-[1,3] dioxolane; Or represent thiazole-2 at A, and under the situation of 5-two bases, suitable shielded thiazole derivative, for example methanesulfonic 5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters or 5-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole; Or at A Biao Shi oxazole-2, under the situation of 5-two bases, suitably Shou protects De oxazole derivative, for example 2-chloromethyl-5-(2-methyl-[1,3] dioxolane-2-yl)-oxazoles, or formula Ms-O-CH 2-A-C (OR x) 2-(C 1-C 3) alkyl or Cl-CH 2-A-C (OR x) 2-(C 1-C 3) another suitable reagent of alkyl.
The reagent that also can use ethylene glycol for example in the presence of the reagent of for example TsOH in the solvent of for example toluene under about 110 ℃ temperature by R 2Expression-CO-(C 1-C 3) compound of structure 2 of alkyl obtains the compound of structure 6; Or use for example LiBF 4And the reagent of trimethyl orthoformate in the solvent of for example ethylene glycol under about 95 ℃ temperature by R 2Expression-CO-(C 1-C 3) compound of structure 2 of alkyl obtains the compound of structure 6.
Perhaps; can with part A .b) described in program similar; the reagent that then uses ethylene glycol for example in the presence of the reagent of for example TsOH in the solvent of for example toluene under about 110 ℃ temperature with the ketone group protective group, by the compound of the synthetic structure 6 of compound of structure 5.Perhaps, can use for example LiBF 4And the reagent of trimethyl orthoformate is carried out ketal formation under about 95 ℃ temperature in the solvent of for example ethylene glycol.
Can seemingly use following each thing with the compounds of those structures 5: show oxazole-2 at the A table, under the situation of 5-two bases, oxazole derivative, for example 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-5-chloromethyl-oxazole; Or at A Biao Shi oxazole-2, under the situation of 4-two bases, suitably Shou protects De oxazole derivative; methanesulfonic 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-base methyl esters for example; by commercially available 4-nitro-2H-[1,2,3] triazole (people such as T.E.Eagles; Organic preparations and procedures 2 (2); 117-119,1970, P.N.Neuman J.Heterocycl.Chem.8; 51-56,1971) compound of preparation structure 7.
Can use following program to prepare 2-(5-chloromethyl-furans-2-yl)-2-methyl-[1,3] dioxolane: a) to reach for example LiBF at trimethyl orthoformate 4Catalyzer have down in the solvent of for example ethylene glycol protection commercially available 1-furans-2-base-ethyl ketone under about 95 ℃ temperature; B) organolithium reagent with for example n-Butyl Lithium carries out lithiumation and adds DMF subsequently under about-78 ℃ temperature in the solvent of for example THF; C) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under about 0 ℃ temperature, reduce; And d) use (for example) methane sulfonyl chlorine at for example Et 3The alkali of N and DMAP exists down at for example CH 2Cl 2Solvent under about 0 ℃ temperature with pure chlorination.
Can use following program to prepare 1-(5-chloromethyl-isoxazole-3-bases)-ethyl ketone: a) to use (for example) tertiary butyl dimethylsilyl chlorine in the solvent of for example T HF, protecting 5-hydroxymethyl-isoxazoles-3-ethyl formate in the presence of the alkali of for example imidazoles; B) reductive agent with for example DiBAL reduces under subambient temperature in the solvent of for example THF; C) under the standard oxidation condition, use for example MnO 2Reagent in the solvent of for example AcCN under the temperature of about room temperature with pure oxidation; D) under about 0 ℃ temperature at for example CH 2Cl 2Solvent in add trimethyl aluminium; E) under the standard oxidation condition, use for example MnO 2Reagent in the solvent of for example AcCN under the temperature of about room temperature with pure oxidation; F) reach for example LiBF at trimethyl orthoformate 4Catalyzer exist down in the solvent of for example ethylene glycol under about 95 ℃ temperature and the silylation protecting group to be gone protection; G) use (for example) methane sulfonyl chlorine at for example Et 3The alkali of N and DMAP exists down at for example CH 2Cl 2Solvent under about 0 ℃ temperature with pure chlorination.
Can use following program to prepare 2-(5-chloromethyl-thiophene-2-yl)-2-methyl-[1,3] dioxolane: a) with the organolithium reagent of for example n-Butyl Lithium at N, N, N ', N '-tetramethyl--quadrol exists down to be made commercially available 2-methyl-2-thiophene-2-base-[1,3] dioxolane lithiumation and adds DMF subsequently under about-78 ℃ temperature in the solvent of for example THF; B) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under about 0 ℃ temperature, reduce; C) use (for example) methane sulfonyl chlorine at for example Et 3The alkali of N and DMAP exists down at for example CH 2Cl 2Solvent under about 0 ℃ temperature with pure chlorination.
Can prepare methanesulfonic 6-(2-methyl-[1 by following program, 3] dioxolane-2-yl)-and pyridine-2-base methyl esters: a) make commercially available 2, the organolithium reagent of 6-dibromo pyridine and for example n-Butyl Lithium is reaction and subsequently with N,N-dimethylacetamide acetylize under-78 ℃ of temperature to the room temperature range under-78 ℃ temperature approximately in the solvent of for example ether; B) reach for example LiBF at trimethyl orthoformate 4Catalyzer exist and in the solvent of for example ethylene glycol, under about 95 ℃ temperature, to carry out ketal down and form; C) in the solvent of for example ether, under-78 ℃ temperature approximately, carry out lithiumation with the organolithium reagent of for example n-Butyl Lithium and subsequently with the DMF formylation; D) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under the temperature of about room temperature, reduce; E) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3The alkali of N and DMAP exists down carry out methylsulfonylization under about 0 ℃ temperature.
Can prepare methanesulfonic 2-(2-methyl-[1 by following program, 3] dioxolane-2-yl)-and the pyridin-4-yl methyl esters: a) make commercially available 2, the organolithium reagent of 4-dibromo pyridine and for example n-Butyl Lithium is reaction and subsequently with N under-78 ℃ temperature approximately in the solvent of for example ether, the acetylize under-78 ℃ of temperature to the room temperature range of N-dimethyl-methane amide; B) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under the temperature of about room temperature, reduce; C) use tertiary butyl dimethylsilyl chlorine in the solvent of for example methylene dichloride, protecting alcohol in the presence of the alkali of for example imidazoles; D) organolithium reagent that makes protected alcohol and for example n-Butyl Lithium reaction and under-78 ℃ temperature approximately in the solvent of for example ether subsequently with N,N-dimethylacetamide acetylize under-78 ℃ of temperature to the room temperature range; E) reach for example LiBF at trimethyl orthoformate 4Catalyzer exist and in the solvent of for example ethylene glycol, under about 95 ℃ temperature, to carry out ketal down and form; F) in the solvent of for example THF, under the temperature about room temperature or 0 ℃ the silylation protecting group gone protection under the standard conditions of for example TBAF; G) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3The alkali of N and DMAP exists down carry out methylsulfonylization under about 0 ℃ temperature.
Can be by making commercially available 1-methylcyclopentanol and bromine at for example K 2CO 3Alkali exist down and in the solvent of for example chloroform, under about 0 ℃ temperature, react, then in the presence of the catalyzer of for example TsOH with the ethylene glycol protection, thereby prepare 2-(4-bromo-butyl)-2-methyl-[1,3] dioxolane.
Can be as described for methanesulfonic 6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters, but with commercially available 1, the 3-dibromobenzene is initial methanesulfonic 3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl ester for preparing.
Can be as described for methanesulfonic 6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters, but with commercially available 2, the 4-dibromo pyridine is initial methanesulfonic 4-(2-methyl-[1, the 3] dioxolane-2-yl)-pyridine-2-base methyl esters for preparing.
Can prepare methanesulfonic 2-ethanoyl-pyridin-4-yl methyl esters by following program: a) make commercially available 2, the organolithium reagent of 4-dibromo pyridine and for example n-Butyl Lithium is reaction and subsequently with N under-78 ℃ temperature approximately in the solvent of for example ether, the dinethylformamide formylation; B) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under the temperature of about room temperature, reduce; C) in the presence of the silylation protective material of for example tertiary butyl dimethylsilyl chlorine at for example CH 2Cl 2Solvent in the presence of the alkali of for example imidazoles, protect; D) in the solvent of for example ether, under-78 ℃ temperature approximately, carry out lithiumation with the organolithium reagent of for example n-Butyl Lithium and subsequently with the N,N-dimethylacetamide acetylize; E) for example using, the fluorizating agent of TBAF goes the silyl ether derivative to protect in the solvent of for example THF under the temperature of about room temperature; And f) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3The alkali of N and DMAP exists down carry out methylsulfonylization under about 0 ℃ temperature.
Can be as (2-methyl-[1,3] dioxolane-2-yl)-the pyridin-4-yl methyl esters be described for methanesulfonic 2-, but with commercially available 2,4-two bromo-thiazoles are initial methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters for preparing.
Can be as described for 2-(5-chloromethyl-furans-2-yl)-2-methyl-[1,3] dioxolane, but be initial 2-(4-chloromethyl-thiophene-2-yl)-2-methyl-[1, the 3] dioxolane for preparing with commercially available 1-(4-bromo-2-thienyl)-second-1-ketone.
Can prepare 4-chloromethyl-thiazole-2-ethyl formate by following program: commercially available careless amino acid ethyl ester and lawesson reagent (Lawesson ' s reagent) are reacted under about 80 ℃ temperature in the solvent of for example toluene; And b) with 1, the 3-Dichloro acetone is cyclisation under about 110 ℃ temperature in the solvent of for example toluene.
Can pass through A.b) following described program, then reach for example LiBF at trimethyl orthoformate 4Catalyzer exist and in the solvent of for example ethylene glycol, under about 90 ℃ temperature, to carry out ketal down and form, thereby prepare 4-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole by 4-chloro-methyl-thiazole-2-ethyl formate.
Can prepare 2-chloromethyl-5-methane sulfonyl-furans by following program: commercially available 5-nitro-furans-2-ethyl formate and sodium methyl mercaptide are reacted under about 100 ℃ temperature in the solvent of for example DMSO; B) with the oxygenant of for example m-CPBA at for example CH 2Cl 2Solvent under the temperature of about room temperature, carry out oxidation; C) reductive agent with for example DiBAL reduces under subambient temperature in the solvent of for example THF; And d) reagent that uses methane sulfonyl chlorine for example in the solvent of for example methylene dichloride at for example Et 3Under existing, the alkali of N and DMAP under about 0 ℃ temperature, carries out chlorination.
Can prepare methanesulfonic 5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters by following program: a) commercially available 2-bromo-thiazole-5-formaldehyde and trimethyl aluminium are reacted under about 0 ℃ temperature in the solvent of for example methylene dichloride; B) with for example MnO 2Oxygenant in the solvent of for example acetonitrile, under the temperature of about room temperature, carry out oxidation; C) reach for example LiBF at trimethyl orthoformate 4Catalyzer exist and in the solvent of for example ethylene glycol, under about 95 ℃ temperature, to carry out ketal down and form; D) in the solvent of for example ether, under-78 ℃ temperature approximately, carry out lithiumation with the organolithium reagent of for example n-Butyl Lithium and subsequently with N, the dinethylformamide formylation; E) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under the temperature of about room temperature, reduce; F) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3The alkali of N and DMAP exists down carry out methylsulfonylization under about 0 ℃ temperature.
Can prepare 5-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole by following program: a) with for example NaBH 4Reductive agent in the solvent of for example MeOH under the temperature of about room temperature the reduction commercially available 2-bromo-thiazole-5-formaldehyde; B) use tertiary butyl dimethylsilyl chlorine at for example CH 2Cl 2Solvent in the presence of the alkali of for example imidazoles protection alcohol; C) in the solvent of for example ether, under-78 ℃ temperature approximately, carry out lithiumation with the organolithium reagent of for example n-Butyl Lithium and subsequently with the N,N-dimethylacetamide acetylize; D) reach for example LiBF at trimethyl orthoformate 4Catalyzer exist and in the solvent of for example ethylene glycol, under about 95 ℃ temperature, to carry out ketal down and form; E) for example using, the fluorizating agent of TBAF goes the silyl ether derivative to protect in the solvent of for example THF under the temperature of about room temperature; And f) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3Under existing, the alkali of N and DMAP under about 0 ℃ temperature, carries out chlorination.
Can be as (2-methyl-[1,3] dioxolane-2-yl)-thiazole be described for 5-chloromethyl-2-, but be initial 2-(5-chloromethyl-thiene-3-yl-)-2-methyl-[1, the 3] dioxolane for preparing with commercially available 4-bromo-thiophene-2-formaldehyde.
Can prepare methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters by following program: a) make commercially available 3-phenyl-acrylamide and 3-bromo-2-oxygen-ethyl propionate at for example NaHCO 3Alkali have down in the solvent of for example THF that the Hang oxazole of Jin forms reaction under about 60 ℃ temperature; B) NaIO that uses (for example) silica gel to support 4Reach for example RuCl 3The metal misfit thing of hydrate carries out oxicracking under the temperature of about room temperature in the solvent of for example methylene dichloride; C) with for example NaBH 4Reductive agent in the solvent of for example EtOH, under about 0 ℃ temperature, reduce; D) use tertiary butyl dimethylsilyl chlorine at for example CH 2Cl 2Solvent in the presence of the alkali of for example imidazoles protection alcohol; E) with the reductive agent of for example DiBAL at for example CH 2Cl 2Solvent in approximately be reduced into aldehyde under-78 ℃ the temperature; F) under about 0 ℃ temperature, react in the solvent of for example methylene dichloride with trimethyl aluminium; G) with for example MnO 2Oxygenant in the solvent of for example acetonitrile, under the temperature of about room temperature, carry out oxidation; H) for example using, the fluorizating agent of TBAF goes the silyl ether derivative to protect in the solvent of for example THF under the temperature of about room temperature; And i) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3The alkali of N and DMAP exists down carry out methylsulfonylization under about 0 ℃ temperature.
Can prepare methanesulfonic 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-base methyl esters by following program: a) make commercially available 3-phenyl-acrylamide and 3-bromo-2-oxygen-ethyl propionate at for example NaHCO 3Alkali have down in the solvent of for example THF that the Hang oxazole of Jin forms reaction under about 60 ℃ temperature; B) NaIO that uses (for example) silica gel to support 4Reach for example RuCl 3The metal misfit thing of hydrate is at for example CH 2Cl 2Solvent under the temperature of about room temperature, carry out oxicracking; C) with for example NaBH 4Reductive agent in the solvent of for example EtOH, under about 0 ℃ temperature, reduce; D) use tertiary butyl dimethylsilyl chlorine at for example CH 2Cl 2Solvent in the presence of the alkali of for example imidazoles protection alcohol; E) reductive agent with for example DiBAL is reduced into alcohol under about 0 ℃ temperature in the solvent of for example THF; F) use the reagent of methane sulfonyl chlorine for example at for example CH 2Cl 2Solvent at for example Et 3The alkali of N and DMAP exists down carry out methylsulfonylization under about 0 ℃ temperature.
Can use following program to prepare 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-5-chloromethyl-oxazole: a) make the city sell the organomagnesium reagent of oxazole with for example isopropyl-magnesium chloride, in the solvent of for example THF, reacting under-15 ℃ the temperature approximately, subsequently with the acetylize under-15 ℃ of temperature to the room temperature range of N-methoxyl group-N-methylacetamide; B) with for example NaBH 4Reductive agent in the solvent of for example MeOH, under the temperature of about room temperature, reduce; C) use tertiary butyl dimethylsilyl chlorine, in the presence of the alkali of for example imidazoles, protection alcohol in the solvent of for example THF; D) organolithium reagent that makes protected alcohol and for example tert-butyl lithium reacts under the temperature in-78 ℃ to-40 ℃ scopes in the solvent of for example THF, and subsequently with N, the formylation under-78 ℃ of temperature to the room temperature range of N-dimethyl-methane amide; E) with for example NaBH 4Reductive agent, in the solvent of for example MeOH, under the temperature of about room temperature, reduce; G) use for example reagent of methane sulfonyl chlorine, at for example CH 2Cl 2Solvent in, at for example Et 3The alkali of N and DMAP exists down, carries out chlorination under about 0 ℃ temperature.
Can use following program to prepare 2-chloromethyl-5-(2-methyl-[1,3] dioxolane-2-yl)-oxazoles: a), in the solvent of for example THF, under about-78 ℃ temperature, to make Shi Shou oxazole lithiumation, and add DMF subsequently with the organolithium reagent of for example n-Butyl Lithium; B) with for example NaBH 4Reductive agent, in the solvent of for example MeOH, under about 0 ℃ temperature, reduce; C) use tertiary butyl dimethylsilyl chlorine, in the presence of the alkali of for example imidazoles, protection alcohol in the solvent of for example THF; D) with the organolithium reagent of for example tert-butyl lithium, in the solvent of for example THF, lithiumation under the temperature in-78 ℃ to-40 ℃ scopes, and subsequently with DMF, formylation under-78 ℃ of temperature to the room temperature range; E) with trimethyl aluminium in the solvent of for example methylene dichloride, under about 0 ℃ temperature, react; F) with for example MnO 2Oxygenant, in the solvent of for example acetonitrile, under the temperature of about room temperature, carry out oxidation; G) reach for example LiBF at trimethyl orthoformate 4Catalyzer exist down, in the solvent of for example ethylene glycol, under about 95 ℃ temperature, form ketal, and remove the silylation protecting group; H) use (for example) Ms-Cl at for example Et 3The alkali of N and DMAP exists down, at for example CH 2Cl 2Solvent in, under about 0 ℃ temperature with pure chlorination.
Formula R 1The chloro-formic ester of-E-COCl or sour muriate or formula R 1The carboxylic acid of-E-COOH can be buied or be synthetic from commercially available phenylformic acid, phenyl aldehyde, benzylalcohol or its heterocyclic analogs according to well-known process (for example).
Also be the formula R of the compound of structure 8 1The acid of-E-COOH is well known in the art or prepare according to hereinafter described method.
Figure BPA00001161879200591
Can be described in route map 1 in the presence of the acid of for example glacial acetic acid, react and prepare R by the aqueous solution that makes 3-oxygen-propanoate ester derivatives and Sodium Nitrite 3The compound of the structure 8 of expression Me.In the presence of the metal chloride of for example mercury chloride of the acid of for example glacial acetic acid and catalytic amount or zinc chloride and zinc powder, oxime is transformed with diacetyl oxide subsequently, then under the dehydration conditions of for example thionyl chloride, in chloroform, carry out cyclisation, then use methods known in the art to make the saponification of ester functional group, this method is for example handled in the solvent of for example ethanol/water or THF or solvent mixture with the alkali of for example NaOH, and then desired acid derivative is provided.Indivedual 3-oxygen-propanoate ester derivatives can be buied or well known.
Figure BPA00001161879200601
Perhaps, can be by making 3-oxygen-propanoate ester derivatives and 4-acetamido-benzenesulfonyl azide reach for example Et described in route map 2 3The solution reaction of the alkali of N prepares the compound of structure 8.For example reach the catalyst treatment of (acetate foundation) two rhodiums (II) dihydrates wantonly with carboxamide derivative subsequently, then use triphenylphosphine and iodine at for example Et 3The alkali of N carries out cyclisation under existing, and then indivedual ester derivatives are provided.Use methods known in the art (for example in the solvent of for example ethanol/water or THF or solvent mixture, handling) to make the saponification of ester functional group, and then desired acid derivative is provided with the alkali of for example NaOH.Indivedual 3-oxygen-propanoate ester derivatives can be buied or well known.
Figure BPA00001161879200611
Perhaps, can be by making formula R described in route map 2b 1Solution of the acid derivative of COOH and isocyano-methyl acetate in the presence of the alkali of for example salt of wormwood sesquialter hydrate or DIPEA and DPPA in the solvent of for example DMF reaction prepare R 3The compound of the structure 8 of expression hydrogen.Use methods known in the art (for example in the solvent of for example ethanol/water or THF or solvent mixture, handling) to make the saponification of ester functional group, and then indivedual acid derivatives are provided with the alkali of for example NaOH.Indivedual sour R 1COOH can buy or well known.
Perhaps, can the reagent of thionyl chloride make 3-phenyl silk amino acid esterification of derivatives under about 0 ℃ temperature in the solvent of for example MeOH by for example using described in route map 3, the standard conditions of then using for example HOBt, DCC, N-methylmorpholine are at for example CH 2Cl 2Solvent under about 0 ℃ temperature with carboxylic acid derivative R 3-COOH coupling prepares the compound of structure 8.Cross the oxygenant of iodine alkane at for example CH with for example Dai Si-Martin (Dess-Martin) 2Cl 2Solvent in oxidation alcohol, then use triphenylphosphine and iodine at for example Et 3The alkali of N carries out cyclisation under existing, and then Ge other oxazole derivative is provided.Can make the saponification of ester functional group by using methods known in the art (for example in the solvent of for example diox, handling), thereby obtain desired acid derivative with the alkali of for example LiOH aqueous solution.
Figure BPA00001161879200621
For example, can obtain R by the program that comprises following item according to route map 4 1(this group is through (C for aryl 1-C 4) alkoxyl group-(C 1-C 2) alkyl replaces) and the compound of structure 8:
■ uses methods known in the art (for example handling in the solvent of for example THF with the alkali of for example LiOH aqueous solution) to make through hydroxyl-(C 1-C 2) 5-phenyl-oxazole derivatives (according to route map 5 or the 6 preparations) saponification that replaces of alkyl;
■ makes the correspondent alcohol alkylation with the alkyl halide of for example alkyl iodide in the solvent of for example DMF in the presence of the alkali of for example NaH;
■ uses methods known in the art (for example handling in the solvent of for example ethanol/water or THF or solvent mixture with the alkali of for example NaOH) to make the saponification of gained ester.
Figure BPA00001161879200631
Route map 4: through (C 1-C 4) alkoxyl group-(C 1-C 2) the 5-phenyl-oxazole derivative (R that replace of alkyl ZExpression (C 1-C 4) alkyl and n represent 1 or 2) and synthetic
For example, can obtain through hydroxyl-(C by the program that comprises following item according to route map 5 1-C 2) the 5-phenyl-oxazole derivatives that replace of alkyl:
■ is similar to the described method of route map 2b, reacts Xing to Cheng oxazole by making phenyl-dicarboxylic acid monoesters derivative and isocyano-methyl acetate;
■ uses the ester group (for example by making tertiary butyl ester generation acid-catalyzed cleavage with (for example) TFA) of arbitrary method selectivity saponification phenyl bond known in the art;
■ is reduced into indivedual primary alconols with the reductive agent as borine with gained acid.
Route map 5: through hydroxyl-(C 1-C 2) the 5-phenyl-oxazole derivatives that replace of alkyl synthetic
Perhaps, can (for example) obtain through hydroxyl-(C by the program that comprises following item according to route map 6 1-C 2) the 5-phenyl-oxazole derivatives that replace of alkyl:
■ makes through hydroxyl-(C by being similar to the described method of route map 2b 1-C 2) benzoic acid derivative that replaces of alkyl and isocyano-methyl acetate react Xing to Cheng oxazole;
Figure BPA00001161879200642
Route map 6: through hydroxyl-(C 1-C 2) the 5-phenyl-oxazole derivatives (2) that replace of alkyl synthetic
Figure BPA00001161879200643
Structure 9
Can be by at first making methyl dichloroacetate and commercially available benzaldehyde derivative R 1-CHO is reacting the compound for preparing structure 9 in the solvent of for example THF in the presence of the alkali of for example KOt-Bu.Described in route map 7, by in the solvent of for example MeCN, transforming (cyclisation) with indivedual thioamides subsequently, then use methods known in the art (for example in the solvent of for example MeOH, handling) to make the saponification of ester functional group, thereby obtain R with the alkali of for example NaOH 3Expression (C 1-C 4) compound of desired structure 9 of alkyl or cyclopropyl.Indivedual phenyl aldehyde R 1-CHO can buy or well known.Thioamides can be buied or can obtain by commercially available carboxylic acid amides is synthetic by lawesson reagent.
Figure BPA00001161879200651
Route map 7: thiazole synthesizes (1), wherein R 3Expression (C 1-C 4) alkyl or cyclopropyl
Perhaps, described in route map 8, by making methyl dichloroacetate and commercially available benzaldehyde derivative R 1-CHO in the presence of the alkali of for example KOt-Bu in the solvent of for example THF reaction obtain R 3The compound of the desired structure 9 of expression hydrogen.Transform with commercially available thiocarbamide subsequently, follow alkaline purification, and then amido-thiazole derivative is provided with for example sodium bicarbonate.Use for example CuBr 2Cu (II) derivative carry out Sang De mayer (Sandmeyer) and transform, then at for example Pd/C, Pt/C or PtO 2Metal catalyst exist hydrogenation take place down, and then provide desired ester.Can use methods known in the art (for example in the solvent of for example MeOH, handling) to carry out the saponification of ester functional group with the alkali of for example NaOH.
Figure BPA00001161879200661
No matter when acquisition is formula (I) compound of enantiomeric mixture form, can use method known to those skilled in the art to separate this enantiomer: for example by forming diastereoisomeric salt and separating or (R, R) chiral stationary phase of (10 μ m) post, DaicelChiralCel OD-H (5-10 μ m) post or Daicel ChiralPak IA (10 μ m) or AD-H (5 μ m) post is reached by Regis Whelk-O1 for example by HPLC.The representative condition of chirality HPLC is that flow velocity is that (EtOH is at for example Et for 0.8 to 150mL/min eluent A 3The amine of N or diethylamine exist or non-existent situation under) with eluent B (hexane) etc. the degree mixture.
Embodiment
Experimental section
The abbreviation (such as in this paper and the above description use)
The Ac ethanoyl
AcCl ethanoyl chlorine
The AcCN acetonitrile
AcOH acetate
Aq. the aqueous solution
The atm normal atmosphere
The Boc tert-butoxycarbonyl
The BSA bovine serum albumin
The Bu butyl
The BuLi n-Butyl Lithium
Ca. about
Cat. catalysis
DCC N, N '-dicyclohexyl carbodiimide
The DIPEA diisopropylethylamine
DiBAL Di-Isobutyl alanate
DMAP 4-N, the N-Dimethylamino pyridine
The DMF dimethyl formamide
The DMSO dimethyl sulfoxide (DMSO)
DPPA diphenylphosphine acyl group azide
The EA ethyl acetate
The EIA enzyme immunoassay
EDC N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride
The ELSD evaporative light scattering detection
Eq. equivalent
The ES+ electron spray(ES), positive ion electrospray from
The Et ethyl
The ether ether
Et 3The N triethylamine
EtOH ethanol
FC silica gel rapid column chromatography
H hour
HBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
The hept heptane
The HOBt hydroxybenzotriazole
The HPLC high performance liquid chromatography
The LC-MS liquid chromatography-mass spectrography
Between m-CPBA-the chlorine peroxybenzoic acid
The Me methyl
MeOH methyl alcohol
Min minute
The MPLC medium pressure liquid chromatography
The MS mass spectrum
The Ms methane sulfonyl
NMO N-methyl-morpholine-N-oxide compound
The NMR nucleus magnetic resonance
The OAc acetate
Org. organic
P is right
P-TsOH is right-toluenesulphonic acids
The PG protecting group
PyBOP benzotriazole-1-base-oxygen base-three-Pyrrolizidine base ,-Phosphonium-hexafluoro-phosphoric acid salt
Rochelle salt (Rochelle ' s salt) Seignette salt
The rf retention factor
The rt room temperature
Sat. saturated
The SCX strong cation exchanger
Sol. solution
TBA four-normal-butyl ammonium
TBAF fluoridizes four-normal-butyl ammonium
The TBDMS tertiary butyl-dimethyl-silylation
The TBDPS tertiary butyl-phenylbenzene-silylation
TBTU O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea a tetrafluoro borate
The tBu tertiary butyl
The TFA trifluoroacetic acid
The THF tetrahydrofuran (THF)
TIPS three-sec.-propyl-silylation
The TLC thin-layer chromatography
TMS trimethylammonium-silylation
The high ruthenic acid tetrapropyl ammonium of TPAP
t RResidence time
TsOH tosic acid monohydrate
The UV ultraviolet ray
The Vis visible light
The I chemistry
General provisions: all temperature with degree centigrade (℃) expression.Unless refer else, take place otherwise be reflected under the room temperature.
As the SCX material, use SiliaBond from Silicycle
Figure BPA00001161879200711
SCX.
With the 0.2mm plate: Merck silica gel 60 F 254Carry out analysis mode thin-layer chromatography (TLC).With 0.2 or the 0.5mm plate: Merck silica gel 60 F 254Be prepared type thin-layer chromatography (TLC).With UV or with KMnO 4(3g), K 2CO 3(20g), NaOH 5% (3mL) and H 2The solution of O (300mL), postheating detects.
Use silica gel 6O Merck (0.063-0.200mm) or Macherey-Nagel silica gel (0.063-0.200mm) to carry out rapid column chromatography (FC) and filtration; With EA, heptane, CH 2Cl 2, CHCl 3, MeOH or its mixture come wash-out.
Use is from the Isolute of International sorbent technology
Figure BPA00001161879200721
SPE Flash SI II post carries out MPLC, with EA, heptane, CH 2Cl 2, MeOH or its mixture come wash-out.
LC-MS-condition 01 (if not indication in addition): analyze: Thermo Finnigan MSQ SurveyorMS with Agilent1100 binary pump and DAD.Post: from the Zorbax SB-AQ 5 μ m of Agilent Technologies, 4.6 * 50mm ID.Eluent: A:H 2O+0.04% TFA; B:AcCN; Gradient: through 1 minute 5%B → 95%B.Flow velocity: 4.50mL/min.Detect: UV/Vis+MS, t RMinute to provide.
LC-MS-condition 02 (if not indication in addition): analyze: Thermo Finnig an MSQ Plus MS with Agilent1100 binary pump and DAD.Post: from the Zorbax SB-AQ 5 μ m of Agilent Technologies, 4.6 * 50mm ID.Eluent: A:H 2O+0.04%TFA; B:AcCN; Gradient: through 1 minute 5%B → 95%B.Flow velocity: 4.50mL/min.Detect: UV/Vis and/or ELSD+MS, t RMinute to provide.
LC-MS-condition 05 (if not indication in addition): analyze: Dionex GHP3200 binary pump, MS:Thermo MSQ Plus, DAD:Dionex PDA3000, ELSD:Sedere Sedex 85.Post: from the XbridgeC18 5 μ M of Waters, 4.6 * 50mm ID, it is constant temperature in Dionex TCC-3200 compartment.Eluent: A:H 2O+0.04%TFA; B:AcCN.Method: gradient: through 1.0 minutes 5%B → 95%B.Flow velocity: 4.5mL/min.Detect: UV/Vis and/or ELSD and MS, t RMinute to provide.
LC-MS-condition 05b (if not indication in addition): analyze: Dionex GHP3200 binary pump, MS:Thermo MSQ Plus, DAD:Dionex PDA3000, ELSD:Sedere Sedex 85.Post: from the Zorbax Extend C18 1.8 μ M of AgilentTechnologies, 4.6 * 20mm, it is constant temperature in Dionex TCC-3200 compartment.Eluent: A:H 2O+0.04%TFA; B:AcCN.Method: gradient: through 1.0 minutes 5%B → 95%B.Flow velocity: 4.5mL/min.Detect: UV/Vis and/or ELSD and MS, t RMinute to provide.
Preparation HPLC: from the X-Bridge C18 5 μ m of Waters, 50 * 19mm ID.Eluent: A:H 2O+0.5%NH 4OH; B:AcCN; Gradient: through 5 minutes 10%B → 90%B.Flow velocity: 40.0mL/min.Detect: UV/Vis and/or ELSD.
Chiral analysis type HPLC:a) Regis Whelk post, 4.6 * 250mm, 10 μ m.Eluent A:EtOH+0.05%Et 3N.Eluent B: hexane.Flow velocity: 1mL/min.b)ChiralPak?AD，4.6×250mm，5μm。Eluent A:EtOH+0.05%Et 3N.Eluent B: hexane.Flow velocity: 1mL/min.c)ChiralCel?OD，4.6×250mm，10μm。Eluent A:EtOH+0.1%Et 3N.Eluent B: hexane.Flow velocity: 0.8mL/min.
Chirality preparation HPLC: a) Regis Whelk 01 post, 50 * 250mm.Flow velocity: 100mL/min.b)ChiralPak?AD，20×250mm。Flow velocity: 10mL/min.c)ChiralCel?OD，20μm，50mm×250mm。Flow velocity: 100mL/min.
NMR:Bruker Avance 400 (400MHz); VarianMercury 300 (300MHz); With respect to used solvent, chemical shift provides with pp m; Multiplicity: s=is unimodal; The d=doublet; The t=triplet; The q=quartet; The p=quintet; The hex=sextet; The hept=septet; The m=multiplet; The br=broad peak; Coupling constant provides with Hz.
Following example illustrates the present invention but does not limit its category fully.
Universal program
Universal program A: acid amides coupling:
In vial, at inert atmosphere (N 2) under, in the acid (1.5 equivalent) of weighing in vial, add aminotriazole (1.0 equivalent) in CH 2Cl 2In solution (0.1M).Add HOBt (2.0 equivalent), DMAP (0.25 equivalent) and DIPEA (2.0 equivalent) in CH 2Cl 2(every mmol HOBt, the 10mL) solution in then add EDC (1.5 equivalent).With gained mixture stirred overnight at room temperature.Reaction mixture is poured into contains (every g Isolute through 1M HCl
Figure BPA00001161879200741
, 1.0mL) diatomite of Chu Liing is (from the Isolute of Separtis
Figure BPA00001161879200742
HM-N) on the syringe.With CH 2Cl 2(3 * 1mL) eluted product and under reduced pressure remove solvent.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program B: dioxolane goes protection (1):
In vial, at inert atmosphere (N 2) under, with 1N HCl (2.7 equivalent) handle dioxolane (1.0 equivalent) in THF 0.07M solution and at room temperature stirred reaction mixture until finishing.Add water and with EA with the product extracting twice.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program C: dioxolane goes protection (2):
(every 0.05mmol dioxolane 70mg) and with reaction mixture at room temperature stirs 18h to add SCX silica gel in the vial that contains the 0.05M solution of dioxolane in MeOH.Filtering mixt and under reduced pressure remove solvent.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program D: amido formate forms (1):
Step 1:
In vial, at inert atmosphere (N 2) under, handle alcohol (1.3 equivalent) in CH with carbonyl chloride (1.3 equivalents, 20% solution in toluene) 2Cl 2In 0.065M solution.With gained mixture stirred overnight at room temperature.Then, reaction mixture is poured into contains (every gIsolute through 1M NaOH
Figure BPA00001161879200751
, 1.25mL) diatomite of Chu Liing is (from the Isolute of Separtis
Figure BPA00001161879200752
HM-N) on the syringe.With CH 2Cl 2(3 * 1mL) eluted product and under reduced pressure remove solvent.
Step 2:
With suitable aminotriazole derivatives (1.0 equivalent) and DIPEA (2.0 equivalent) in CH 2Cl 2(every mmol aminotriazole derivatives, 20mL) the solution-treated chloro-formic ester in and with gained mixture stirred overnight at room temperature.Reaction mixture is poured into contains (every g Isolute through 1M HCl
Figure BPA00001161879200753
, 1.0mL) diatomite of Chu Liing is (from the Isolute of Separtis
Figure BPA00001161879200754
HM-N) on the syringe.With CH 2Cl 2(3 * 1mL) eluted product and under reduced pressure remove solvent.Provide the compound of wanting by HPLC purifying resistates.
Universal program E: ester hydrolysis:
Handle the 0.5M solution of indivedual carboxylicesterss (1.0 equivalent) in 3: 1 mixtures of the corresponding alkyl alcohol of THF and for example MeOH or EtOH with the 1M NaOH aqueous solution (2.0 equivalent).After stirring 3h, form white suspension and under reduced pressure remove organic volatile.Remaining mixture with water (half of the amount of 3: 1 mixtures of THF and MeOH) dilution, is come acidifying (pH=3-4) with the ice bath cooling and by adding the 1M HCl aqueous solution.Filtering suspension liquid and with the cold water washing resistates so that desired carboxylic acid derivatives to be provided after drying.
Synthesizing of universal program F:2-ethanoyl amido-3-oxygen-propanoate ester derivatives:
Figure BPA00001161879200761
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, the 2.5M solution of indivedual 3-oxygen-propanoate ester derivatives (1.0 equivalent) in glacial acetic acid is cooled to 10 ℃ and add NaNO under this temperature 2The 8.2M solution of (1.16 equivalent) Yu Shuizhong.After finishing (15min) in interpolation, make solution be warming up to room temperature and stir 2h.Then, solution is poured in the water (volume of glacial acetic acid 5.3 times) and after several minutes crystal begin to occur.Cool off this suspension and collect crystal with ice bath by filtering.With cold water for several times with filter cake washing, and by with toluene under reduced pressure component distillation remove water so that indivedual 2-hydroxyl imide bases-3-oxygen-propanoate ester derivatives to be provided, it is dissolved in diacetyl oxide and glacial acetic acid (for 1.0mmol other 3-oxygen-propanoate ester derivatives, in 1: 1.3 mixture 0.66mL).In this solution, add sodium acetate (0.06 equivalent) and HgCl 2(0.002 equivalent).Make mixture backflow 1h, then be cooled to room temperature and filtration.With ether flushing solid, organic filtrate is reclaimed, with water washing 3 times and with 1M K 2CO 3Solution washing once.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.By FC purifying crude product so that desired 2-ethanoyl amido-3-oxygen-propanoate ester derivatives to be provided.
Universal program G: cyclisation (1):
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, in ice/NaCl bathes, the indivedual 2-ethanoyl amidos-1.6M solution of 3-oxygen-propanoate ester derivatives (1.0 equivalent) in chloroform is cooled to about 0 ℃.With SOCl 2(1.4 equivalent) is added in stirred solution and temperature is maintained at about 0 ℃ and assigned 30 minutes.Then, solution was stirred 1 hour under refluxing.Add other 0.25 normal SOCl 2And reaction mixture was refluxed 1 hour again.With 1M K 2CO 3The aqueous solution is ended excessive SOCl 2With water layer with twice of extracted with diethyl ether.With the organic phase that merged with water washing once and through MgSO 4Drying is filtered and is under reduced pressure removed solvent the oxazole derivative is provided to provide.
Universal program H: cyclisation (2):
Figure BPA00001161879200781
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with Et 3N (4.1 equivalent) follows indivedual 2-(carbonyl-amino)-3-oxygen-propanoate ester derivatives (1.0 equivalent) in CH 2Cl 2In 0.1M solution be added into triphenylphosphine (2.0 equivalent) and iodine (2.0 equivalent) in CH 2Cl 2In 0.2M solution in.At room temperature reaction mixture is stirred 1.5h.Under reduced pressure remove solvent and Yao the oxazole derivative to provide by F C purifying resistates.
Universal program I:N inserts:
Figure BPA00001161879200782
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, through 1.5h with diazo derivative (1.0 equivalent) in 1,0.5M solution in the 2-ethylene dichloride is added into carboxamide derivative (1.0 equivalent) and rhodium acetate (II) (four (acetate foundation) two rhodiums (II) dihydrates, 0.05 equivalent) in 1, (every mmol carboxamide derivative is 3mL) in the reflux solution in for the 2-ethylene dichloride.Then, under refluxing, reaction mixture is stirred 1.5h.Under reduced pressure remove solvent and by F C purifying resistates so that desired 2-(carbonyl-amino)-3-oxygen-propanoate ester derivatives to be provided.
Universal program J: diazotization:
Figure BPA00001161879200791
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with 4-acetamido benzenesulfonyl azide (1.0 equivalent), then with Et 3N (3.0 equivalent) handles the 0.17M solution of 3-oxygen-propanoate ester derivatives (1.0 equivalent) in AcCN.At room temperature reaction mixture is stirred 1h.Under reduced pressure remove solvent, wet-milling resistates and filtration in ether-sherwood oil.Under reduced pressure remove solvent and wanted the diazo derivative to provide by FC purifying resistates.
Universal program K: gram comes gloomy condensation (Claisen condensation)
Figure BPA00001161879200792
A) be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with several DMF, then handle acid derivative (1.0 equivalent) in 1, the 1.3M solution in the 2-ethylene dichloride with oxalyl chloride (1.3 equivalent).Reaction mixture is at room temperature stirred 3h, then stir 20min down at 80 ℃.Under reduced pressure remove solvent.
B) be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 10 ℃ with magnesium chloride (2.5 equivalent) handle monoethyl malonate sylvite (2 equivalent) in acetonitrile 0.83M solution and suspension stirred 30min down and at room temperature stirs 3h at 10 ℃.With reaction mixture be cooled to 0 ℃ and through 15min with the sour muriatic solution that under A, prepares, then with Et 3N (2 equivalent) dropwise handles.At room temperature gained suspension is stirred 20h.Under reduced pressure remove solvent and with toluene strips residual thing.With resistates be dissolved in toluene (every mmol monoethyl malonate sylvite, 1.5mL) in and under 10 ℃ to handle with the 4M HCl of toluene same amount.With organic layer with 4M HCl, water washing twice, through MgSO 4Solvent is filtered and under reduced pressure removed to drying.Wanted derivative to provide by FC purifying resistates.
Universal program L: dioxolane goes protection (3):
In the vial that contains the 0.05M solution of dioxolane in MeOH, add silica gel bonded tosic acid (every 0.05mmol dioxolane, 70mg, R60530B silica gel bonded tosic acid from Silicycle), and with reaction mixture at room temperature stir 18h.Filtering mixt.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program M: cyclisation (3):
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with salt of wormwood sesquialter hydrate or DIPEA (1.2 equivalent to 1.5 equivalent), then with 2.0M solution-treated acid (1.0 equivalent) the 0.5M solution in DMF in of isocyano-methyl acetate (1.5 equivalent to 3.2 equivalent) in DMF, and mixture at room temperature stirred 5min.Reaction mixture is cooled to 0 ℃ and with the 0.67M solution-treated of DPPA (1.1 equivalent) in DMF.Gained suspension is stirred 2h down and at room temperature stirs 15h at 0 ℃.Then, it is poured in 1: 1 mixture of EA and toluene, and with organic layer with water, 10% citric acid, water and saturated NaHCO 3Solution washing.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.Wanted derivative to provide by FC purifying resistates.
Universal program N: dioxolane goes protection (4):
In vial, at inert atmosphere (N 2) under, with the 0.1M solution of formic acid (volume same) processing dioxolane (1.0 equivalent) Yu Shuizhong with water, and at the following stirred reaction mixture of the temperature (be preferably room temperature) of scope between 0 ℃ and 50 ℃.Use 1N NaOH that the pH value is adjusted to 8-9 and with EA with the product extracting twice.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program O: amido formate forms (2):
In vial, at inert atmosphere (N 2) under, to suitable aminotriazole derivatives (1.0 equivalent) in AcCN (or CH 2Cl 2) in solution (0.05M solution) in add chloroformic acid 4-nitro phenyl ester (1.1 equivalent) and DIPEA (1.0 equivalent).Under inert atmosphere, mixture is stirred 30min, and it is transferred in the vial that contains suitable alcohol (1.4 equivalent) subsequently.After adding DIPEA (1.0 equivalent), mixture is stirred 12h down at 60 ℃.Reaction mixture is poured into contains (every g Isolute through 1M NaOH
Figure BPA00001161879200811
, 1.25mL) diatomite of Chu Liing is (from the Isolute of Separtis
Figure BPA00001161879200812
HM-N) on the syringe.With CH 2Cl 2(3 * 1mL) eluted product.Under reduced pressure remove solvent.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program P: jesse greener addition:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, handle the 0.1M solution of aldehyde (1.0 equivalent) in THF with suitable cyclopropyl or alkyl magnesium bromide (4.0 equivalent).Reaction mixture is stirred 90min down and at room temperature stirs 45min at-78 ℃, subsequently by being poured into saturated NH 4End in the Cl aqueous solution, with EA extraction, and with the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.Provide the compound of wanting by Fc purifying resistates.
Universal program Q: alcohol oxidation:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature handle alcohol (1.0 equivalent) in CH with NMO (3.0 equivalent) 2Cl 2In 0.1M solution and reaction mixture stirred 5min.Then add TPAP (0.1 equivalent), and reaction mixture is at room temperature stirred 2h and under reduced pressure removes solvent subsequently.Provide the compound of wanting by Fc purifying resistates.
Universal program R: condensation:
Figure BPA00001161879200821
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, the solution of aldehyde derivatives (1 equivalent) in two chloro-methyl acetates (1.0 equivalent) is added in the 1.45M suspension of KOt-Bu (1.0 equivalent) in THF through 1h.Reaction mixture is stirred down 5h and stirred overnight at room temperature at-78 ℃.Under reduced pressure remove solvent and be dissolved in resistates among the EA and with water washing.With organic layer through MgSO 4It is dry and under reduced pressure concentrated so that corresponding 3-chloro-2-oxygen-methyl propionate derivative to be provided.
Universal program S: cyclisation (4):
Figure BPA00001161879200831
R 3Expression (C 1-C 4) alkyl or cyclopropyl.
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 0.5M solution and the molecular sieve of indivedual thioamides (1.0 equivalent) in MeCN
Figure BPA00001161879200832
(every mmol thioamides 91mg) is added in the 2.2M solution of indivedual 3-chloro-2-oxygen-propanoate ester derivatives (1.0 equivalent) in MeCN.After at room temperature stirring 5h, with the ice bath cooling mixture and filter out the throw out that obtained.Resistates is washed with cold MeCN, in addition dry, be dissolved in MeOH (as be used for the MeCN of thioamides 1.12 times of amount) and stir 6h down at 50 ℃.Under reduced pressure remove solvent so that corresponding thiazole-4-carbamate derivatives to be provided.
Universal program T: cyclisation (5):
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, the 0.57M solution of 3-chloro-2-oxygen-propanoate ester derivatives (1.0 equivalent) in acetone is added in the 0.72M solution of thiocarbamide (1.0 equivalent) in acetone.With reaction mixture 57 ℃ of following stirred overnight.Filter institute's refrigerative reaction mixture and under reduced pressure remove solvent.Resistates is dissolved in the water to obtain 0.2M solution, with it with saturated NaHCO 3The aqueous solution is handled until reaching pH 7.Then, with the extracted with diethyl ether mixture, organic layer is merged, through MgSO 4Dry and under reduced pressure remove solvent so that desired 2-amino-thiazolyl-derivative to be provided.
Universal program U: sandmeyer reaction (SandMeyer reaction):
Figure BPA00001161879200841
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 5 ℃, with Isopentyl nitrite (1.45 equivalent) exercise due diligence CuBr 2(0.97 equivalent) 0.18M solution in AcCN.Reaction mixture is stirred 30min and then adds 2-amino-thiazolyl--4-carbamate derivatives (0.86 equivalent) by part.The gained mixture is at room temperature stirred 15min, then stir 30min down and stir 1h down at 65 ℃ at 40 ℃.Under reduced pressure remove solvent and wanted the bromo derivative to provide by FC purifying resistates.
Universal program V: go halogenation:
Figure BPA00001161879200842
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at H 2Under the atmosphere, with Pd/C (10%Pd, for the 1mmol bromide, 200mg) the reduction 0.16M solution of bromide (1.0 equivalent) in EtOH.Through the diatomite filtration reaction mixture and under reduced pressure remove solvent so that desired reductive derivative to be provided.
Universal program W: esterification:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, handle acid (1.0 equivalent) 1M solution in MeOH with thionyl chloride (1.1 equivalent).Then, with gained mixture stirred overnight at room temperature.Under reduced pressure remove volatile matter and with resistates wet-milling and filter compound is provided to provide in EA.Provide the compound of wanting by FC or HPLC purifying resistates.
Universal program X: acid amides coupling:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, handle acid (1.0 equivalent) in CH with HOBt (1.1 equivalent), DCC (1.1 equivalent), N-methylmorpholine (1.5 equivalent) and amine (1 equivalent) 2Cl 2In 0.2M solution.The gained mixture is at room temperature stirred 2h, be poured into 5%KHSO 4In, stir 15min, filtered and with CH 2Cl 2Washing.With CH 2Cl 2Aqueous phase extracted and with the organic phase that merged with saturated NaHCO 3The aqueous solution, salt water washing are through MgSO 4Solvent is filtered and under reduced pressure removed to drying.The purifying resistates provides title compound.
Universal program Y: cyclisation:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, cross iodine alkane (1.0 equivalent) and handle acid amides (1 equivalent) in CH with Dai Si-Martin 2Cl 2In 0.13M solution.The gained mixture is at room temperature stirred 1h and the short embolism by alkali alumina (active I) and sand to be filtered to and to contain triphenylphosphine (2.02 equivalent), I 2(2.0 equivalent) and Et 3N (4.0 equivalent) is in CH 2Cl 2In the flask of the new system solution in (with amount identical in oxidation step).With CH 2Cl 2Washing leaching cake.Behind 15min, reaction mixture is transferred to separating funnel, with saturated Na 2S 2O 3The aqueous solution is handled and with CH 2Cl 2Extraction.With organic layer with saturated NaHCO 3Solution washing is filtered, and under reduced pressure removes solvent.The purifying resistates provides the compound of wanting.
Universal program Z: ester hydrolysis:
Handle the 0.2M solution of indivedual carboxylicesterss (1.0 equivalent) in 1: 1 mixture of the corresponding alkyl alcohol of THF and for example MeOH or EtOH with the 1M NaOH aqueous solution (5.0 equivalent), and at room temperature stirred reaction mixture until finishing.Come acidified reaction mixture (pH=3-4) and extract mixture by adding the 1M HCl aqueous solution with EtOAc.With the organic extract that merged through MgSO 4Drying is filtered, and under reduced pressure remove solvent after drying, to provide the carboxylic acid derivative of being wanted.
Universal program Z1: acid amides coupling:
In vial, at inert atmosphere (N 2) under, handle the 0.04M solution of carboxylic acid lithium (1.0 equivalent) in DMF with HATU (1.0 equivalent), and reaction mixture is at room temperature stirred 10min.Then, add the 0.07M solution of amine (1.0 equivalent) in DMF, then add DIPEA (2.84 equivalent), and at room temperature stir the gained mixture until finishing.Add water and with EtOAc with the water layer extracting twice.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.Provide the compound of wanting by FC or HPLC purifying resistates.
Synthesizing of intermediate
5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-methyl-formiate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (2.66g 14.47mmol), follows K with 5-chloromethyl-furans-2-methyl-formiate 2CO 3(9.18g, 65.75mmol) and the TBA bromide (848mg 2.63mmol) handles 4-nitro-2H-[1,2,3] triazole (1.50g, 13.15mmol) solution in acetone (26.3mL).With reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent, add water (50mL) and with EA (3 * 30mL) extraction products, with the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily: TLC:rf (50: 50 heptane EA)=0.22 in 50: 50 by FC.LC-MS-condition 02:t R=0.90min.
[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (4.36mL, the 1M solution in toluene 4.36mmol) are dropwise handled 5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-methyl-formiate (325mg, 1.28mmol) solution in THF (13.0mL) with DiBAL under-10 ℃.Reaction mixture is stirred 1h down at-10 ℃, then at room temperature stir 1h.Add saturated Rochelle salt (Rochelle ' s salt) aqueous solution (40mL) and reaction mixture is at room temperature stirred 1h.With EA (2 * 30mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided title compound in 50: 50: TLC:rf (50: 50 heptane-EA)=0.28 by FC.LC-MS-condition 02:t R=0.77min.
5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(644mg 6.67mmol) handles [5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-methyl alcohol (248mg, 1.11mmol) solution in AcCN (11.0mL).With reaction mixture stirred overnight at room temperature, subsequently by diatomite filtration and under reduced pressure remove solvent.(heptane-EA) the purifying resistates provided title compound in 40: 60: TLC:rf (40: 60 heptane-EA)=0.26 by FC.LC-MS-condition 02:t R=0.84min.
1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-ethanol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, ((4-nitro-[1,2,3] triazole-2-ylmethyl)-(180mg is 0.81mmol) in CH for furans-2-formaldehyde 0.64mmol) to handle 5-for 0.32mL, the 2M solution in heptane with trimethyl aluminium under-10 ℃ 2Cl 2Solution (8.0mL).Reaction mixture is stirred 2h down at 0 ℃, then be poured into saturated NH 4On the Cl aqueous solution (5mL), with CH 2Cl 2(10.0mL), then 1N HCl (10mL) dilution.With CH 2Cl 2(2 * 20mL) extraction mixtures.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 50: 50 heptane-EA) provides the title compound that is yellow oily: TLC:rf (50: 50 heptane-EA)=0.31 by FC.LC-MS-condition 02:t R=0.82min.
1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(238mg 2.47mmol) handles 1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-ethanol (98mg, 0.41mmol) solution in AcCN (4.0mL), and reaction mixture at room temperature stirred 2 days, pass through diatomite filtration subsequently.Under reduced pressure remove solvent so that the title compound of the solid state that is white in color to be provided.LC-MS-condition 02:t R=0.86min.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and Dien-Rodney Stark device (Dean-Stark) in flame-dried round-bottomed flask, with trimethyl orthoformate (0.17mL, 1.52mmol) and LiBF4 (14mg, 0.15mmol) processing 1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-furans-2-yl]-ethyl ketone (180mg, 0.76mmol) in ethylene glycol (0.85mL, 15.24mmol) solution in.Gained mixture heating up to 95 is ℃ overnight.Make reaction mixture be cooled to room temperature.Add NaHCO 3(10mL) and EA (10mL) and with EA (2 * 10mL) aqueous phase extracted.The organic extract that is merged is washed with salt solution (10mL), through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 60: 30 heptane-EA) provides the title compound that is colorless oil: TLC:rf (60: 30 heptane-EA)=0.31 by FC.LC-MS-condition 02:t R=0.94min; [M+H] +=281.01.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole (218mg, 0.78mmol), iron powder (132mg, 2.33mmol) and NH 4(210mg, 3.89mmol) mixture in the mixture of EtOH (4.0mL) and water (2.0mL) stirs 0.5h down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(20mL), then add 1MNaOH (20mL).With CH 2Cl 2(2 * 20mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.71min; [M+H] +=251.16.
2-furans-2-base-2-methyl-[1,3] dioxolane:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with trimethyl orthoformate (100.0mL, 908.0mmol), then LiBF 4(7.00g 75mmol) handles 1-furans-2-base-ethyl ketone (50.00g, 454.0mmol) solution in ethylene glycol (500.0mL).Heating is overnight down at 95 ℃ with reaction mixture.Add saturated NaHCO 3The aqueous solution (500mL) and with EA (500mL) extraction mixture.(2 * 250mL) washings are through MgSO with salt solution with organic extract 4Solvent is filtered and under reduced pressure removed to drying.Provide the title compound that is colorless oil by distillation purifying resistates (11 millibars, 71-73 ℃).
[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to n-BuLi (14.6mL, 1.6M solution in hexane, 23.35mmol) dropwise add 2-furans-2-base-2-methyl-[1,3] dioxolane (3.00g, 19.46mmol) solution in THF (6.0mL) in the solution in THF (21mL).Then, reaction mixture is stirred down 1h at-78 ℃, dropwise add subsequently DMF (4.52mL, 58.38mmol).Reaction mixture is stirred 1h down at-78 ℃.Add saturated NH 4The Cl aqueous solution (50mL) and with EA (2 * 50mL) extraction mixtures.With the organic extract that merged through MgSO 4Drying is filtered and is under reduced pressure removed solvent and is the thick 5-of orange buttery (2-methyl-[1,3] dioxolane-2-yl)-furans-2-formaldehyde so that 5.91g to be provided.LC-MS-condition 02:t R=0.75min; [M+H] +=183.23.At inert atmosphere (N 2) under with thick substance dissolves in MeOH (59.0mL) and under 0 ℃ through 20min with NaBH 4(1.53g, 38.92mmol, 5 equal portions) are by a part processing.Reaction mixture is at room temperature stirred 45min.Reaction mixture is poured on the water (80mL), and with EA (2 * 60mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided title compound in 50: 50: TLC:rf (50: 50 heptane-EA)=0.27 by FC.LC-MS-condition 02:t R=0.65min; [M+H] +=185.28.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (3.14mL, 22.59mmol), then DMAP (212mg, 1.74mmol) and Ms-Cl (1.62mL 20.85mmol) handles that [5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-yl]-(3.20g is 17.37mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (32.0mL).After at room temperature stirring 2h, reaction mixture is ended with water (30mL), with CH 2Cl 2(30mL) extraction, and with the organic extract that merged through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be the thick 2-of brown buttery (5-chloromethyl-furans-2-yl)-2-methyl-[1,3] dioxolane so that 4.49g to be provided.At inert atmosphere (N 2) under, with 4-nitro-2H-[1,2,3] and triazole (1.97g, 17.27mmol), K 2CO 3(7.16g, 51.82mmol), then the TBA bromide (1.11g 3.45mmol) handles thick material in acetone (43mL).Reaction mixture was at room temperature stirred 2 days.Add water (30mL), then add EA (40mL).With EA (40mL) aqueous layer extracted and with the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 60: 40 heptane-EA) provides and is orange buttery title compound: TLC:rf (60: 40 heptane-EA)=0.28 by FC.LC-MS-condition 02:t R=0.95min; [M+H] +=281.01.
2-(5-chloromethyl-furans-2-yl)-2-methyl-[1,3] dioxolane:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (3.44mL, 22.80mmol), then DMAP (232mg, 1.90mmol) and Ms-Cl (1.77mL 22.80mmol) handles that [5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-yl]-(3.50g is 19.00mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (35.0mL).After at room temperature stirring 2h, reaction mixture is ended with water (40mL), with CH 2Cl 2(40mL) extraction, and with the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent.By FC (8: 2: 0.1 heptane-EA-Et 3N) the purifying resistates provides the title compound that is yellow oily: TLC:rf (4: 1 heptane-EA)=0.35.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with DIPEA (2.63mL 15.34mmol) handles 4-nitro-2H-[1,2,3] triazole (875mg, 7.67mmol) solution in DMF (7.0mL).Behind the 30min, add 2-(5-chloromethyl-furans-2-yl)-2-methyl-[1,3] dioxolane (1.87g, 9.21mmol) solution in DMF (7.0mL) and reaction mixture stirred 16h down at 50 ℃.Add water (100mL), then add EA (100mL).With EA (100mL) aqueous layer extracted and with the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 2: 1 heptane-EA) provides and is orange buttery title compound: TLC:rf (2: 1 heptane-EA)=0.26 by FC.LC-MS-condition 02:t R=0.95min; [M+H] +=281.01.
The 6-bromo-oneself-2-ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with K 2CO 3(33.11g, (4.00g is 39.94mmol) in CHCl 239.62mmol) to handle commercially available 1-methylcyclopentanol 3Solution (130mL) and reaction mixture stirred 15min.(10.23mL 199.68mmol) and with reaction mixture stirs 2.5h down at 0 ℃ then to add bromine.Reaction mixture slowly is poured into through the saturated Na of ice refrigerated 2S 2O 3On the aqueous solution (100mL).(2 * 250mL) washings are through MgSO with water with organic layer 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of gradient heptane → 75: 25 heptane-EA) provides the title compound that is yellow oily: TLC:rf (75: 25 heptane-EA)=0.36 by FC. 1H?NMR(400MHz，CDCl 3)δ1.66-1.80(m，2H)，1.82-1.93(m，2H)，2.15(s，3H)，2.48(t，J＝7.3Hz，2H)，3.41(t，J＝6.5H?z，2H)。
2-(4-bromo-butyl)-2-methyl-[1,3] dioxolane:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and Dien-Rodney Stark device in flame-dried round-bottomed flask, with ethylene glycol (10.4mL, 186.92mmol) and TsOH (35mg, 0.19mmol) handle the 6-bromo-oneself-2-ketone (3.34g, 18.65mmol) solution in toluene (71.3mL).Reaction mixture is heated to backflow, lasts 3h, make it be cooled to room temperature, and add saturated NaHCO 3The aqueous solution (100mL) and ether (100mL), and with water with water (2 * 100mL) washing, through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that title compound to be provided. 1H?NMR(400MHz，CDCl 3)δ1.34(s，3H)，1.50-1.65(m，2H)，1.65-1.75(m，2H)，1.84-1.98(m，2H)，3.43(t，J＝6.8Hz，2H)，3.90-4.04(m，4H)。
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-butyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-(4-bromo-butyl)-2-methyl-[1,3] dioxolane (215mg, 0.96mmol) the solution-treated 4-nitro-2H-[1 in AcCN (1.0mL), 2,3] triazole (100mg, 0.88mmol) and Cs 2CO 3(315mg, 0.96mmol) solution in AcCN (1.0mL).Reaction mixture is stirred 16h down at 80 ℃.Add water (20mL), then add EA (30mL).With EA (30mL) aqueous layer extracted and with the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided title compound in 2: 1: TLC:rf (2: 1 heptane-EA)=0.33 by FC.LC-MS-condition 02:t R=0.92min.
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-butyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-butyl]-4-nitro-2H-[1,2,3] triazole (250mg, 0.98mmol), iron powder (165mg, 2.93mmol) and NH 4(264mg, 4.88mmol) mixture in the mixture of EtOH (3.0mL) and water (1.5mL) stirs 30min down at 85 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(20mL), then add water (20mL).With CH 2Cl 2(2 * 20mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is light yellow oily to be provided.LC-MS-condition 02:t R=0.66min; [M+H] +=227.47.
[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to commercially available 2-methyl-2-thiophene-2-base-[1,3] dioxolane (5.00g, 28.49mmol) dropwise add N, N, N ' in the solution in THF (145.0mL), N '-tetramethyl--quadrol (4.41mL, 29.06mmol), then add n-BuLi (18.14mL, 1.6M solution in hexane, 29.06mmol), Wen-Du is remained on-78 ℃.Then, reaction mixture is stirred down 2h at-78 ℃, dropwise add subsequently DMF (6.74mL, 87.22mmol).Remove cooling bath and reaction mixture is stirred 16h.Reaction mixture is poured into saturated NaH 4On the Cl aqueous solution (200mL), and with EA (2 * 200mL) extractions.With the organic extract that merged through MgSO 4Drying is filtered and is under reduced pressure removed solvent so that thick 5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-formaldehyde that is yellow oily to be provided.LC-MS-condition 02:t R=0.87min; [M+AcCN] +=240.32.At inert atmosphere (N 2) under, with thick substance dissolves in MeOH (51.2mL) and under 0 ℃ through 20min with NaBH 4(1.35g, 34.19mmol, 5 equal portions) are by a part processing.Reaction mixture is at room temperature stirred 45min.Reaction mixture is poured on the water (90mL), and with EA (2 * 225mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided title compound in 50: 50: TLC:rf (50: 50 heptane-EA)=0.40 by FC.LC-MS-condition 02:t R=0.73min; [M+H] +=201.46.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (2.26mL, 16.23mmol), then DMAP (152mg, 1.25mmol) and Ms-Cl (1.16mL 14.98mmol) handles that [5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-yl]-(2.5g is 12.48mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (25.0mL).Reaction mixture is at room temperature stirred 2h, end with water (30mL) subsequently, with CH 2Cl 2(50mL) extraction, and with the organic extract that merged through MgSO 4Drying is filtered, and solvent thick 2-(5-chloromethyl-thiophene-2-yl)-2-methyl-[1,3] dioxolane to provide 2.16g to be yellow oily under reduced pressure is provided.At room temperature, with through DIPEA (2.76mL, 16.13mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (226mg, 2.00mmol) solution of the thick material of solution-treated (2.11g) in DMF (15mL) in DMF (15.0mL).With the gained mixture 50 ℃ of following stirred overnight.Add water (100mL), then add EA (100mL).Organic extract is washed with water (100mL), through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 2: 1 heptane-EA) provides the title compound of the solid state that is white in color: TLC:rf (2: 1 heptane-EA)=0.17 by FC.LC-MS-condition 02:t R=0.98min; [M+H] +=297.08.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole (1.09g, 3.68mmol), iron powder (623mg, 11.05mmol) and NH 4(995mg, 18.41mmol) mixture in the mixture of EtOH (10.0mL) and water (5.0mL) stirs 20min down at 85 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(30mL), then add 1MNaOH (30mL).With CH 2Cl 2(2 * 20mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.78min; [M+H] +=267.30.
1-(3-bromo-phenyl)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (4.0mL, the 2.5M solution in hexane 10.00mmol) handle 1,3-dibromobenzene (2.45g, 10.07mmol) suspension in THF (25.0mL) with n-BuLi under-78 ℃.Reaction mixture is stirred 30min, and (1.50mL 16.13mmol) and then makes solution be warming up to room temperature through 1h to add N,N-dimethylacetamide subsequently.Then add saturated NH 4The Cl aqueous solution and with Et 2O (3 * 50mL) aqueous layer extracted, and with the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 20: 1 heptane-EA) provides the title compound of the solid state that is white in color: TLC:rf (10: 1 heptane-EA)=0.28 by FC.LC-MS-condition 02:t R=0.95min.
2-(3-bromo-phenyl)-2-methyl-[1,3] dioxolane:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with trimethyl orthoformate (1.50mL, 13.68mmol), then LiBF 4(131mg, (1360mg is 6.83mmol) in ethylene glycol (8.00mL, 143.46mmol) solution in 1.37mmol) to handle 1-(3-bromo-phenyl)-ethyl ketone.Reaction mixture is heated 15h down at 95 ℃.Add saturated Na 2CO 3The aqueous solution and with mixture with twice of extracted with diethyl ether and with the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.Provide the title compound that is light yellow oily: TLC:rf (10: 1 heptane-EA)=0.34 by FC (20: 1 heptane-E A) purifying resistates.LC-MS-condition 02:t R=1.01min.
3-(2-methyl-[1,3] dioxolane-2-yl)-phenyl aldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to 2-(3-bromo-phenyl)-2-methyl-[1,3] dioxolane (944mg, 3.88mmol) dropwise add in the solution in THF (20.0mL) n-BuLi (1.60mL, the 2.5M solution in hexane, 4.00mmol).Then, reaction mixture is stirred down 30min at-78 ℃, dropwise add subsequently DMF (0.40mL, 5.17mmol).Make reaction mixture be warming up to room temperature through 1h.Add saturated NH 4The Cl aqueous solution and with mixture with Et 2O extraction three times.With the organic extract that merged through NaSO 4Drying is filtered, and is under reduced pressure removed solvent so that the thick title compound that is light yellow oily to be provided.LC-MS-condition 02:t R=0.87min.
[3-(2-methyl-[1,3] dioxolane-2-yl)-phenyl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, to 3-(2-methyl-[1,3] dioxolane-2-yl)-(896mg 4.66mmol) adds NaBH in the ice-cold solution in MeOH (10.0mL) to phenyl aldehyde 4(228mg, 5.79mmol, 4 equal portions).Then, at room temperature reaction mixture is stirred 1h.Add water and with EA with twice of mixture extraction.With the organic extract that merged with the salt water washing, through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying so that the title compound that is colorless oil: TLC:rf to be provided (50: 50 heptane-EA)=0.28.LC-MS-condition 02:t R=0.74min; [M+H] +=195.71.
Methanesulfonic 3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl ester:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃ with Et 3N (0.75mL, 5.33mmol), then DMAP (49mg, 0.41mmol) and Ms-Cl (0.40mL 5.15mmol) handles that [3-(2-methyl-[1,3] dioxolane-2-yl)-phenyl]-(786mg is 4.05mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (10.0mL).After stirring 1h under 0 ℃, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided the title compound of the solid state that is white in color in 80: 20 to 20: 10 by FC.LC-MS-condition 02:t R=0.91min.
2-[3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with DIPEA (0.15mL 0.87mmol) handles 4-nitro-2H-[1,2,3] triazole (50mg, 0.43mmol) solution in DMF (1.0mL).Behind the 30min, add (106mg, 0.52mmol) solution in DMF (1.0mL) and reaction mixture stirred 3 days down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 2: 1 heptane-EA) provides the title compound that is colorless oil: TLC:rf (1: 2 heptane-EA)=0.42 by FC.LC-MS-condition 02:t R=0.99min.
2-[3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl]-4-nitro-2H-[1,2,3] triazole (33mg, 0.11mmol), iron powder (19mg, 0.34mmol) and NH 4(31mg, 0.57mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 1h down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1N NaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through Na 2SO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.78min; [M+H] +=261.13.
6-(4-nitro-[1,2,3] triazole-2-yl)-oneself-2-ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with DIPEA (0.34mL 2.00mmol) handles 4-nitro-2H-[1,2,3] triazole (114mg, 1.00mmol) suspension in DMF (1.0mL).After 30 minutes, add the 6-bromo-oneself-2-ketone (179mg, 1.00mmol) solution in DMF (1.0mL) and reaction mixture stirred 24h down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 2: 1 heptane-EA) provides the title compound that is yellow oily: TLC:rf (2: 1 heptane-EA)=0.26 by FC.LC-MS-condition 02:t R=0.86min.
2-(5,5-two fluoro-hexyls)-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with 6-(4-nitro-[1,2,3] triazole-2-yl)-oneself-2-ketone (118mg, solution 0.56mmol) be dissolved in (diethylin) sulphur trifluoride (0.15mL, 1.11mmol) in and with reaction mixture 50 ℃ of following stirred overnight.Reaction mixture is poured on the ice (20mL), and with mixture with CH 2Cl 2(2 * 20mL) extractions are with water (30mL), salt solution (30mL) washing, through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 4: 1 heptane-EA) provides the title compound that is yellow oily: TLC:rf (4: 1 heptane-EA)=0.32 by FC.LC-MS-condition 02:t R=1.01min.
2-(5,5-two fluoro-hexyls)-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 85 ℃ with 2-(5,5-two fluoro-hexyls)-4-nitro-2H-[1,2,3] triazole (and 71mg, 0.30mmol), iron powder (51mg, 0.91mmol) and NH 4(82mg, 1.52mmol) mixture in the mixture of EtOH (1.0mL) and water (0.5mL) stirs 20min to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add water (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.79min; [M+H] +=205.54.
5-methyl sulfenyl-furans-2-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature (2.05g 27.82mmol) handles commercially available 5-nitro-furans-2-ethyl formate (5.00g, 27.01mmol) solution in DMSO (34.5mL) with methyl mercaptan acid sodium.Then, with mixture 100 ℃ of following stirred overnight, at room temperature with saturated NH 4The Cl aqueous solution (250mL) is handled and with EA (3 * 100mL) aqueous layer extracted.With saturated NaHCO 3The organic extract that the aqueous solution (100mL) and salt solution (100mL) washing are merged is through MgSO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided title compound in 70: 30: TLC:rf (70: 30 heptane-EA)=0.52 by FC.LC-MS-condition 02:t R=0.96min; [M+AcCN+H] +=228.23.
5-methane sulfonyl-furans-2-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature (3.28g, 13.32mmol) (1.74g is 9.34mmol) in CH for exercise due diligence 5-methyl sulfenyl-furans-2-ethyl formate with a CPBA 2Cl 2Solution (16.0mL).Then, mixture is at room temperature stirred 2h, at room temperature with saturated Na 2CO 3Aqueous solution processing and Yi Shui and salt water washing organic layer are through MgSO 4Drying is filtered and is under reduced pressure removed solvent so that the title compound that is the yellow solid shape to be provided.LC-MS-condition 02:t R=0.83min.
(5-methane sulfonyl-furans-2-yl)-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃ with DiBAL-H (19.50mL, the 1M solution in THF, 19.50mmol) handle 5-methane sulfonyl-furans-2-ethyl formate (1.26g) in THF (57.0mL) solution and reaction mixture stirred 2h under this temperature.Reaction mixture is poured into Rochelle salt (100mL) goes up and at room temperature stir 12h.With EA (2 * 100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 30: 70 heptane-EA) provides the title compound that is yellow oily: TLC:rf (30: 70 heptane-EA)=0.28 by FC.LC-MS-condition 02:t R=0.50min.
2-(5-methane sulfonyl-furans-2-ylmethyl)-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃ with Et 3N (0.71mL, 5.11mmol), then DMAP (50mg, 0.39mmol) and Ms-Cl (0.37mL, (692mg is 3.93mmol) in anhydrous CH 4.71mmol) to handle (5-methane sulfonyl-furans-2-yl)-methyl alcohol 2Cl 2Solution (7.0mL).After at room temperature stirring 2h, reaction mixture is ended with water (10mL), with CH 2Cl 2(20mL) extraction, and with the organic extract that merged through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be the thick 2-chloromethyl-5-methane sulfonyl-furans of yellow oily so that 868mg to be provided.To be added into (0.27mL in this thick material of the 183mg among the DMF (0.7mL) through DIPEA, 1.59mmol) 4-nitro-2H-[1 of pre-treatment 1h, 2,3] triazole (90mg, 0.79mmol) in the solution in DMF (0.7mL), and reaction mixture at room temperature stirred 48h.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 4: 6 heptane-EA) provides the title compound that is yellow oily: TLC:rf (4: 6 heptane-EA)=0.36 by FC.LC-MS-condition 02:t R=0.85min.
2-(5-methane sulfonyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 85 ℃, with 2-(5-methane sulfonyl-furans-2-ylmethyl)-4-nitro-2H-[1,2,3] triazole (62mg, 0.23mmol), iron powder (39mg, 0.68mmol) and NH 4(62mg, 1.14mmol) mixture in the mixture of EtOH (1.0mL) and water (0.5mL) stirs 30min to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add water (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.63min; [M+H] +=243.27.
4-bromo-thiazole-2-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, (5.9mL, the 2.5M solution in hexane 14.72mmol) are handled commercially availablely 2, and (3.50g is 14.41mmol) in anhydrous Et for 4-two bromo-thiazoles with n-BuLi 2Solution among the O (120mL).Reaction mixture is stirred 30min under this temperature.Then add N, and dinethylformamide (1.35m L, 14.47mmol) and make mixture be warming up to room temperature in period at 1h.By adding saturated NH 4The Cl aqueous solution (50mL) stopped reaction.Separate all layers and with Et 2O (3 * 50mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(10: 1-＞heptane-EA) the purifying resistates provided the title compound that is the light yellow solid shape in 3: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.21.LC-MS-condition 02:t R=0.81min.
(4-bromo-thiazol-2-yl)-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (1.68g 8.75mmol) is dissolved among the MeOH (10mL) with 4-bromo-thiazole-2-formaldehyde.Add a NaBH by part down at 0 ℃ 4(428mg 10.86mmol) and with reaction mixture at room temperature stirs 1h.Add water (10mL) and with EA (3 * 20mL) extraction mixtures.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(6: 1-＞heptane-EA) the purifying resistates provided the title compound that is the light yellow solid shape in 2: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.31.LC-MS-condition 02:t R=0.62min[M+H] +=194.31.
4-bromo-2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (1.37g 7.06mmol) is dissolved in anhydrous CH with (4-bromo-thiazol-2-yl)-methyl alcohol 2Cl 2(21mL).0 ℃ add down tertiary butyl dimethylsilyl chlorine (1.17g, 7.77mmol), then add imidazoles (985mg, 14.47mmol).Reaction mixture is at room temperature stirred 2h.Add 10%K 2CO 3The aqueous solution (10mL) separates all layers and with CH 2Cl 2(2 * 20mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is colorless oil to be provided.TLC:rf (1: 1 heptane-EA)=0.80.
1-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiazole-4-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to 4-bromo-2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-(1.94g is 6.29mmol) in anhydrous Et for thiazole 2Add in the solution among the O (50mL) n-BuLi (2.76mL, the 2.5M solution in hexane, 6.92mmol).Then, reaction mixture is stirred down 30min at-78 ℃, dropwise add subsequently N,N-dimethylacetamide (1.17mL, 12.58mmol).Make reaction mixture be warming up to room temperature in period and under this temperature, stir 20min at 1h.Add saturated NH 4The Cl aqueous solution (20mL) separates all layers, and with Et 2O (3 * 30mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(20: 1-＞heptane-EA) the purifying resistates provided the title compound that is the yellow solid shape in 5: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.51.LC-MS-condition 02:t R=1.11min; [M+H] +=272.39.
2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-4-(2-methyl-[1,3] dioxolane-2-yl)-thiazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (1.46mL 13.29mmol), follows LiBF with trimethyl orthoformate 4(125mg 1.30mmol) handles 1-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiazole-4-yl]-ethyl ketone (1.77g, 6.52mmol) solution in ethylene glycol (7mL).Reaction mixture is heated 4h down at 95 ℃.Add saturated Na 2CO 3The aqueous solution (5mL) and with Et 2O (2 * 20mL) extraction mixtures.With organic extract through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(20: 1-＞heptane-EA) the purifying resistates provided and is brown buttery title compound in 3: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.56.LC-MS-condition 02:t R=1.11min; [M+H] +=316.36.
[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (6.2mL, the 1M solution in THF 6.20mmol) are handled 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-4-(2-methyl-[1 with TBAF under 0 ℃, 3] dioxolane-2-yl)-thiazole (1.30g, 4.12mmol) solution in anhydrous THF (10mL).Reaction mixture is descended to stir 5min and at room temperature stirred 1 hour 30 minutes at 0 ℃.Then, with EA (10mL) dilution, (3 * 10mL) washings are through MgSO with salt solution with mixture 4Drying is filtered and is under reduced pressure concentrated.(5: 1-＞heptane-EA) the purifying resistates provided the title compound that is yellow oily in 1: 3 by FC.TLC:rf (1: 2 heptane-EA)=0.20.LC-MS-condition 02:t R=0.59min; [M+H] +=202.48.
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.67mL, 4.79mmol), then DMAP (46mg, 0.37mmol) and Ms-Cl (0.37mL 4.67mmol) handles that [4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl]-(745mg is 3.70mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (5mL).After stirring 1 hour 30 minutes under 0 ℃, with water (5mL) stopped reaction.With organic layer through MgSO 4Drying is filtered, and thick methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-the yl)-thiazol-2-yl methyl esters of solvent to provide 1.03g (quantitatively) to be yellow oily under reduced pressure is provided.To be added into (0.36mL in this thick material (323mg) of the part among the DMF (2.0mL) through DIPEA, 2.10mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (120mg, 1.05mmol) in the solution in DMF (2.0mL), and reaction mixture stirred 24h down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 1: 2 heptane-EA) provides the title compound that is yellow oily: TLC:rf (1: 2 heptane-EA)=0.33 by FC.LC-MS-condition 02:t R=0.88min, [M+H] +=298.16.
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole (145mg, 0.49mmol), iron powder (83mg, 1.46mmol) and NH 4(132mg, 2.44mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 1h down at 75 ℃ to Cl.Filtered while hot reaction mixture and with the EtOH flush cake.Concentrated filtrate and the resistates branch is dissolved in CH under reduced pressure 2Cl 2(10mL) with the 1M NaOH aqueous solution (10mL) in.With CH 2Cl 2(2 * 10mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily (120mg, 92%) to be provided.LC-MS-condition 02:t R=0.68min, M+H] +=268.05.
1-(2-bromo-pyridin-4-yl)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, (5.85mL, the 2.5M solution in hexane 14.6mmol) are handled commercially availablely 2, and (3.30g is 13.9mmol) in anhydrous Et for 4-two bromo-pyridines with n-BuLi 2Suspension among the O (75mL).Reaction mixture is stirred 30min under this temperature.Then add N, and N-dimethyl-ethanamide (2.6mL, 27.9mmol) and make mixture be warming up to room temperature in period and under this temperature, stir 30min at 1h.By adding saturated NH 4The Cl aqueous solution (50mL) stopped reaction.Separate all layers and with Et 2O (2 * 50mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound of the solid state that is white in color in 20: 1 to 5: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.41.LC-MS-condition 02:t R=0.81min; [M+H] +=200.61.
2-bromo-4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (1.85mL 16.88mmol) follows LiBF with trimethyl orthoformate 4(158mg 1.65mmol) handles 1-(2-bromo-pyridin-4-yl)-ethyl ketone (1650mg, 8.25mmol) mixture in ethylene glycol (8.8mL).Heating is overnight down at 95 ℃ with reaction mixture.Add saturated Na 2CO 3The aqueous solution (20mL) and with Et 2O (2 * 30mL) extraction mixtures.With organic extract through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 6: 1 to 2: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.57.LC-MS-condition 02:t R=0.88min; [M+H] +=244.19.
4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to 2-bromo-4-(2-methyl-[1,3] dioxolane-2-yl)-(1950mg is 7.99mmol) in anhydrous Et for pyridine 2Add in the solution among the O (40mL) n-BuLi (3.60mL, the 2.5M solution in hexane, 8.79mmol).Then, reaction mixture is stirred down 30min at-78 ℃, dropwise add subsequently DMF (0.75mL, 9.69mmol).Make reaction mixture be warming up to room temperature and under this temperature, stir 10min.Add saturated NH 4The Cl aqueous solution (30mL) separates all layers, and with Et 2O (3 * 30mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is light yellow oily in 10: 1 to 2: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.40.
[4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 4-(2-methyl-[1,3] dioxolane-2-yl)-(1100mg 5.69mmol) is dissolved among the MeOH (15mL) pyridine-2-formaldehyde.Add a NaBH by part down at 0 ℃ 4(278mg 7.05mmol) and with reaction mixture at room temperature stirs 1h.Add water and with EA (3 * 30mL) extraction mixtures.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.41min; [M+H] +=196.51.
Methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.88mL, 6.29mmol), then DMAP (60mg, 0.49mmol) and Ms-Cl (0.49mL 6.15mmol) handles that [4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-yl]-(950mg is 4.87mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (5mL).After at room temperature stirring 2h, with water (5mL) stopped reaction.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 5: 1 to 2: 1 by FC.LC-MS-condition 02:t R=0.76min, [M+H] +=274.30.
4-(2-methyl-[1,3] dioxolane-2-yl)-2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-pyridine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with methanesulfonic 4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters (315mg, 1.15mmol) solution in D MF (2.0mL) is added into (0.36mL through DIPEA, 2.10mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] (120mg 1.05mmol) stirs 48h down at 50 ℃ in the solution in DMF (2.0mL) and with reaction mixture to triazole.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through NaSO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 5: 1 to 1: 4 heptane-EA) provides the title compound that is the light yellow solid shape: TLC:rf (1: 2 heptane-EA)=0.24 by FC.LC-MS-condition 02:t R=0.89min, [M+H] +=292.27.
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 4-(2-methyl-[1,3] dioxolane-2-yl)-2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-pyridine (210mg, 0.71mmol), iron powder (120mg, 2.12mmol) and NH 4(191mg, 3.53mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 1h down at 75 ℃ to Cl.Filtered while hot reaction mixture and with the EtOH flush cake.Concentrated filtrate and the resistates branch is dissolved in CH under reduced pressure 2Cl 2(10mL) with the 1M NaOH aqueous solution (10mL) in.With CH 2Cl 2(2 * 10mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(99: 1 to 19: 1CH by FC 2Cl 2-MeOH) the purifying resistates provides and is brown buttery title compound: TLC:rf (19: 1 CH 2Cl 2-MeOH)=0.33.LC-MS：t R＝0.64min，[M+H] +＝262.29。
1-(6-bromo-pyridine-2-yl)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (4.0mL, the 2.5M solution in hexane 10.00mmol) handle 2,6-dibromo pyridine (2.44g, 10.07mmol) suspension in ether (25.0mL) with n-BuLi under-78 ℃.Reaction mixture is stirred 30min, and (1.50mL 16.13mmol) and then makes solution be warming up to room temperature through 1h to add N,N-dimethylacetamide subsequently.Then add saturated NH 4The Cl aqueous solution and with Et 2O (2 * 50mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 20: 1 heptane-EA) provides the title compound of the solid state that is white in color: TLC:rf (20: 1 heptane-EA)=0.25 by FC.LC-MS-condition 02:t R=0.98min.
2-bromo-6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with trimethyl orthoformate (2.10mL, 19.16mmol), then LiBF 4(180mg, (1880mg is 9.40mmol) in ethylene glycol (10.00mL, 179.32mmol) solution in 1.88mmol) to handle 1-(6-bromo-pyridine-2-yl)-ethyl ketone.Reaction mixture is heated 5h down at 95 ℃.Add saturated Na 2CO 3The aqueous solution and with mixture with twice of extracted with diethyl ether and with the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 20: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (50: 50 heptane-EA)=0.57 by FC.
6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, (2-methyl-[1,3] dioxolane-2-yl)-(2.21g is 9.05mmol) in Et for pyridine to 2-bromo-6- 2Dropwise add in the solution among the O (60mL) n-BuLi (3.70mL, the 2.5M solution in hexane, 9.25mmol).Then, reaction mixture is stirred down 30min at-78 ℃, dropwise add subsequently DMF (0.85mL, 11.00mmol).Make reaction mixture be warming up to room temperature through 1h.Add 5%NaHCO 3The aqueous solution and with mixture with Et 2O extraction three times.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.Provide the title compound that is the light yellow solid shape by FC (heptane-EA was to pure EA in 4: 1) purifying resistates.
[6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, to 6-(2-methyl-[1,3] dioxolane-2-yl)-(713mg 3.69mmol) adds NaBH in the ice-cold solution in MeOH (10.0mL) to pyridine-2-formaldehyde 4(180mg, 4.57mmol, 4 equal portions).Then, at room temperature reaction mixture is stirred 1h.Add water and extract mixture, then with 9: 1 extracting twice of EA-MeOH with EA.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is the light yellow solid shape to be provided.LC-MS-condition 02:t R=0.46min; [M+H] +=196.49.
Methanesulfonic 6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.67mL, 4.83mmol), then DMAP (46mg, 0.37mmol) and Ms-Cl (0.37mL 4.72mmol) handles that [6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-yl]-(729mg is 3.74mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (10.0mL).After stirring 1h under 0 ℃, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided the title compound that is light yellow oily in 70: 30 to 50: 50 by FC.LC-MS-condition 02:t R=0.79min; [M+H] +=274.39.
2-(2-methyl-[1,3] dioxolane-2-yl)-6-(4-nitro-[1,2,3] triazole-2-ylmethyl)-pyridine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with methanesulfonic 6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-base methyl esters (164mg, 0.6mmol) solution in DMF (2.0mL) is added into (0.20mL through DIPEA, 1.17mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] (57mg 0.5mmol) stirs 48h down at 50 ℃ in the solution in DMF (1.0mL) and with reaction mixture to triazole.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 4: 1 to 1: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (1: 1 heptane-EA)=0.50 by FC.LC-MS-condition 02:t R=0.90min, [M+H] +=292.35.
2-[6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-(2-methyl-[1,3] dioxolane-2-yl)-6-(4-nitro-[1,2,3] triazole-2-ylmethyl)-pyridine (66mg, 0.23mmol), iron powder (38mg, 0.68mmol) and NH 4(61mg, 1.13mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 1h down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(20mL), then add 1M NaOH (20mL).With CH 2Cl 2(2 * 20mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and under reduced pressure removes solvent and be light green buttery title compound: TLC:rf (EA)=0.50 to provide.LC-MS-condition 02:t R=0.67min; [M+H] +=262.40.
3-(2-hydroxyl-ethyl)-phenylformic acid:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to 3-bromobenzene ethanol (2.34g, 11.29mmol) and N,N,N (3.24mL is 22.58mmol) in Et 2(14.0mL, the 1.6M solution in hexane 22.59mmol), remain on temperature-78 ℃ dropwise to add n-BuLi in the solution among the O (29.0mL).Then, reaction mixture is stirred 2h down at-20 ℃.Then, under-78 ℃, blast anhydrous carbon dioxide gas and reach 10min by reaction mixture.Remove cooling bath and reaction mixture is stirred 1h.With water (50mL) extractive reaction mixture.With 2N HCl with water layer be acidified to pH=1 and with EA (2 * 75mL) extraction.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is the beige solid shape to be provided.LC-MS-condition 02:t R=0.67min.
5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-methyl-formiate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃ with NaH (56mg 1.29mmol) handles 5-[3-(2-hydroxyl-ethyl)-phenyl]-oxazoles-4-formic acid (100mg, the 0.43mmol) solution in DMF (1.0mL), and the gained mixture stirred 45min down at 0 ℃.(0.14mL 2.14mmol) and with reaction mixture at room temperature stirs 45min then to add methyl-iodide.With reaction mixture with saturated NH 4The Cl aqueous solution (20mL) is ended, with EA (2 * 20mL) extractions, and with the organic extract that merged (2 * 20mL) washings are through MgSO with water 4Drying is filtered and is under reduced pressure removed solvent so that title compound to be provided.LC-MS-condition 02:t R=0.92min; [M+H] +=262.38.
5-(3-tert-butoxycarbonyl-phenyl)-oxazoles-4-methyl-formiate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with isocyano-methyl acetate (3.45mL, 36.00mmol) the solution-treated m-phthalic acid list tert-butyl ester in DMF (6.0mL) (4.00g, 18.00mmol) and salt of wormwood sesquialter hydrate (6.03g, 43.20mmol) suspension in DMF (36.0mL).Behind the 5min, reaction mixture is cooled to 0 ℃ and dropwise add DPPA (4.01mL, 18.00mmol) solution in DMF (6mL).The gained mixture is stirred down 2h and stirred overnight at room temperature subsequently at 0 ℃.Add 1: 1 mixture (400mL) of toluene: EA and with organic layer with water (150mL), 10% aqueous citric acid solution (150mL) and saturated NaHCO 3The aqueous solution (150mL) washing.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound of the solid state that is white in color in 60: 40 by FC.TLC:rf (60: 40 heptane-EA)=0.27.LC-MS-condition 02:t R=1.04min, [M+H] +=304.32.
5-(3-carboxyl-phenyl)-oxazoles-4-methyl-formiate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with 5-(3-tert-butoxycarbonyl-phenyl)-oxazoles-4-methyl-formiate (1.00g, 3.30mmol) solution stirring 45min in TFA (13.3mL).Under reduced pressure remove TFA and with resistates at Et 2Wet-milling among the O is filtered and with Et 2The O washing is to provide pulverous title compound that is white in color.LC-MS-condition 02:t R=0.79min, [M+H] +=248.20.
5-(3-hydroxymethyl-phenyl)-oxazoles-4-methyl-formiate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with BH 3(10.1mL, 1M solution in THF 10.11mmol) are dropwise handled 5-(3-carboxyl-phenyl)-oxazoles-4-methyl-formiate (500mg, 2.02mmol) suspension in THF (14.0mL).The gained mixture is stirred 4h down at 0 ℃.Then dropwise add MeOH (14mL).Behind the 30min, under reduced pressure remove solvent.Add EA (20mL) and with organic phase with 1N NaOH (10mL), water (10mL) and salt solution (10mL) washing.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.By FC (93: 7 CH 2Cl 2-MeOH) the purifying resistates provides the title compound of the solid state that is white in color.TLC：rf(93∶7CH 2Cl 2-MeOH)＝0.32。LC-MS-condition 02:t R=0.76min, [M+H] +=234.39.
5-(3-hydroxymethyl-phenyl)-oxazoles-4-formic acid:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, handle 5-(3-hydroxymethyl-phenyl)-oxazoles-4-methyl-formiate (265mg, 1.13mmol) solution in THF (11.0mL) with 1N NaOH (5.5mL).The gained mixture is stirred 1.5h, then with 1N HCl acidifying, with EA (2 * 25mL) extracting twice and the organic phase that is merged with salt solution (10mL) washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound of the solid state that is white in color to be provided.LC-MS-condition 02:t R=0.67min, [M+AcCN+H] +=261.29.
5-(3-methoxymethyl-phenyl)-oxazoles-4-methyl-formiate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (56mg 1.29mmol) handles 5-(3-hydroxymethyl-phenyl)-oxazoles-4-formic acid (100mg, the 0.43mmol) solution in DMF (1.0mL), and the gained mixture stirred 45min down at 0 ℃ with NaH under 0 ℃.(0.14mL 2.14mmol) and with reaction mixture at room temperature stirs 1.5 to add MeI.Add saturated NH 4The Cl aqueous solution (20mL) and with water layer with EA (2 * 20mL) extracting twice.(2 * 10mL) washings are through MgSO with water with the organic layer that merged 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.89min, [M+H] +=248.36.
5-(3-methoxymethyl-phenyl)-oxazoles-4-formic acid:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, handle 5-(3-methoxymethyl-phenyl)-oxazoles-4-methyl-formiate (280mg, 1.13mmol) solution in THF (11.0mL) with 1N NaOH (5.5mL).The gained mixture is stirred 1.5h, then with 1N HCl acidifying, with EA (2 * 20mL) extracting twice and the organic phase that is merged with salt solution (20mL) washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound of the solid state that is white in color to be provided.LC-MS-condition 02:t R=0.77min, [M+AcCN+H] +=275.35.
Amido-thioketones base-ethyl acetate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 80 ℃, with commercially available careless amino acid ethyl ester (43.429g, 370.86mmol) and lawesson reagent (150.00g, 370.86mmol) the solution stirring 2h in toluene (550.0mL).The gained mixture is cooled to room temperature and adds CH 2Cl 2(300mL).Filtering mixt and under reduced pressure remove solvent.By FC (CH 2Cl 2) the purifying resistates provides the title compound that is the orange solids shape.
4-chloromethyl-thiazole-2-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (2.50g, 18.77mmol) with 1, (2.88g, 21.59mmol) mixture in toluene (20.0mL) stirs 2h to 3-two chloro-third-2-ketone with amido-thioketones base-ethyl acetate under refluxing.At room temperature add EtOAc (20mL) and with saturated NaHCO 3The aqueous solution (10mL), then salt solution (20mL) purging compound.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is faint yellow oily in 4: 1 by FC.TLC:rf (4: 1 heptane-EA)=0.26.LC-MS-condition 02:t R=0.89min, [M+H] +=206.40.
(4-chloromethyl-thiazol-2-yl)-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, with DiBAL (36.09mL, 1M solution in THF 36.09mmol) is handled 4-chloromethyl-thiazole-2-ethyl formate (2.47g, 12.03mmol) solution in THF (120.0mL), and reaction mixture is stirred 1h down at-78 ℃, and make it be warming up to room temperature through 1h.Be poured into reaction mixture on the saturated Rochelle's salt solution and at room temperature stir 1h.With EtOAc (2 * 150mL) aqueous layer extracted and the organic layer that is merged with salt solution (200mL) washing.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is faint yellow oily in 1: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.30.LC-MS-condition 02:t R=0.59min, [M+H] +=164.07.
4-chloromethyl-thiazole-2-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with MnO 2(4.73g 49.01mmol) handles (4-chloromethyl-thiazol-2-yl)-methyl alcohol (1.60g, 9.80mmol) solution in AcCN (98.0mL).With reaction mixture stirred overnight at room temperature, subsequently by diatomite filtration and under reduced pressure remove solvent.(heptane-EA) the purifying resistates provided the title compound that is colorless oil in 4: 1 by FC.TLC:rf (4: 1 heptane-EA)=0.37.LC-MS-condition 02:t R=0.77min.
1-(4-chloromethyl-thiazol-2-yl)-ethanol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, (chloromethyl-thiazole-(1.05g is 6.49mmol) in CH for 2-formaldehyde 32.45mmol) to handle 4-for 32.45mL, the 1M solution in heptane with trimethyl aluminium 2Cl 2Solution (65.0mL).Then, reaction mixture is stirred 45min down at 0 ℃.Then add CH 2Cl 2(100.0mL), add saturated NH subsequently 4The Cl aqueous solution (80mL).Then, with 1N HCl (100mL) treating mixture and with CH 2Cl 2(100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.66min, [M+H] +=178.50.
1-(4-chloromethyl-thiazol-2-yl)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with MnO 2(2.97g, (1.09g, the 6.15mmol) solution in AcCN (61.0mL) and reaction mixture at room temperature stirred 16h passes through diatomite filtration subsequently 30.76mmol) to handle 1-(4-chloromethyl-thiazol-2-yl)-ethanol.Under reduced pressure remove solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.84min, [M+H] +=176.41.
4-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and Dien-Rodney Stark device in flame-dried round-bottomed flask, with trimethyl orthoformate (1.24mL, 11.30mmol), LiBF subsequently 4(106mg, (992mg is 5.65mmol) in ethylene glycol (6.30mL, 112.96mmol) solution in 1.13mmol) to handle 1-(4-chloromethyl-thiazol-2-yl)-ethyl ketone.Reaction mixture is heated 2h down at 95 ℃.Add saturated NaHCO 3The aqueous solution (50mL) and with EA (50mL) extraction mixture.(2 * 50mL) washings are through MgSO with salt solution with organic extract 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 4: 1 heptane-EA) provides the title compound that is yellow oily: TLC:rf (4: 1 heptane-EA)=0.30 by FC.LC-MS-condition 02:t R=0.84min, [M+H] +=220.36.
2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-4-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 4-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole (231mg, 1.05mmol) solution in DMF (1.5mL) is added into (0.30mL through DIPEA, 1.75mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (100mg, 0.88mmol) in the solution in DMF (1.5mL), and reaction mixture stirred 48h down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 6: 4 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (6: 4 heptane-EA)=0.33 by FC.LC-MS-condition 02:t R=0.90min, [M+H] +=298.23.
2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-4-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-4-ylmethyl]-4-nitro-2H-[1,2,3] triazole (86mg, 0.29mmol), iron powder (49mg, 0.87mmol) and NH 4(78mg, 1.45mmol) mixture in the mixture of EtOH (1.0mL) and water (0.5mL) stirs 60min down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1N NaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and under reduced pressure removes solvent and be the buttery title compound to provide.LC-MS-condition 02:t R=0.68min; [M+H] +=268.25.
2-bromo-Pyridine-4-Carboxaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, (3.36mL, the 2.5M solution in hexane 8.42mmol) handle 2, and (1.90g is 8.02mmol) in anhydrous Et for 4-two bromo-pyridines with n-BuLi 2Suspension among the O (40mL).Reaction mixture is stirred 30min under this temperature.Then add N, and N-dimethyl-methane amide (0.78mL, 10.03mmol) and make mixture be warming up to room temperature in period and under this temperature, stir 20min at 1h.By adding saturated NH 4The Cl aqueous solution (30mL) stopped reaction.Separate all layers and with Et 2O (3 * 50mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound of the solid state that is white in color in 10: 1 to 2: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.44.
(2-bromo-pyridin-4-yl)-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (904mg 4.86mmol) is dissolved among the MeOH (10mL) with 2-bromo-Pyridine-4-Carboxaldehyde.Add a NaBH by part down at 0 ℃ 4(236mg 5.99mmol) and with reaction mixture at room temperature stirs 1h.Add water (10mL) and with EA (3 * 20mL) extraction mixtures.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound of the solid state that is white in color to be provided.TLC:rf (1: 1 heptane-EA)=0.22.LC-MS-condition 02:t R=0.63min; [M+H] +=188.33.
2-bromo-4-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-pyridine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (780mg 4.15mmol) is dissolved in anhydrous CH with (2-bromo-pyridin-4-yl)-methyl alcohol 2Cl 2(21mL).0 ℃ add down tertiary butyl dimethylsilyl chlorine (688mg, 4.56mmol), then add imidazoles (579mg, 8.50mmol).Reaction mixture is at room temperature stirred 2h.Add 10%K 2CO 3The aqueous solution (10mL) separates all layers and with CH 2Cl 2(2 * 20mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is colorless oil to be provided.TLC:rf (1: 1 heptane-EA)=0.80.LC-MS-condition 02:t R=1.17min; [M+H] +=302.29.
1-[4-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-pyridine-2-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, to 2-bromo-4-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-(1.04g is 3.44mmol) in anhydrous Et for pyridine 2Add in the solution among the O (50mL) n-BuLi (1.60mL, the 2.5M solution in hexane, 3.96mmol).Then, reaction mixture is stirred down 1h at-78 ℃, dropwise add subsequently N,N-dimethylacetamide (0.64mL, 6.88mmol).Make reaction mixture be warming up to room temperature and under this temperature, stir 10min.Add saturated NH 4The Cl aqueous solution (20mL) separates all layers, and with Et 2O (3 * 30mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is light yellow oily in 20: 1 to 5: 1 by FC.TLC:rf (1: 2 heptane-EA)=0.64.LC-MS-condition 02:t R=1.12min; [M+H] +=265.84.
4-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-2-(2-methyl-[1,3] dioxolane-2-yl)-pyridine:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and Dien-Rodney Stark device in flame-dried round-bottomed flask, with trimethyl orthoformate (1.50mL, 13.67mmol), then LiBF 4(128mg 1.34mmol) handles 1-[4-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-pyridine-2-yl]-(1.78g is 6.71mmol) in ethylene glycol (7.14mL, 127.95mmol) solution in for ethyl ketone.Heating is overnight down at 95 ℃ with reaction mixture.Add saturated NaHCO 3The aqueous solution (50mL) and with EA (50mL) extraction mixture.(2 * 50mL) washings are through MgSO with salt solution with organic extract 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is light yellow oily in 20: 1 to 1: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.50.LC-MS-condition 02:t R=0.91min, [M+H] +=310.40.
[2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with TBAF (4.70mL, 1M solution in THF, 4.70mmol) processing 4-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-2-(2-methyl-[1,3] dioxolane-2-yl)-pyridine (840mg, 2.71mmol) solution in anhydrous THF (15mL).Reaction mixture is stirred 5min down and at room temperature stirs 1.5h at 0 ℃.Then, with EA (10mL) dilution, (3 * 10mL) washings are through MgSO with salt solution with mixture 4Drying is filtered and is under reduced pressure concentrated.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 5: 1 to 1: 3 by FC.TLC:rf (1: 2 heptane-EA)=0.10.LC-MS-condition 02:t R=0.33min; [M+H] +=196.54.
Methanesulfonic 2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl methyl esters:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.50mL, 3.56mmol), then DMAP (34mg, 0.27mmol) and Ms-Cl (0.27mL 3.46mmol) handles that [2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl]-(530mg is 2.72mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (5mL).After at room temperature stirring 2h, with water (5mL) stopped reaction.With organic layer through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is the light brown oily in 5: 1 to 2: 1 by FC.TLC:rf (1: 2 heptane-EA)=0.36.
2-(2-methyl-[1,3] dioxolane-2-yl)-4-(4-nitro-[1,2,3] triazole-2-ylmethyl)-pyridine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with methanesulfonic 2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl methyl esters (303mg, 1.11mmol) solution in D MF (2.0mL) is added into (0.35mL through DIPEA, 2.02mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] (115mg 1.01mmol) stirs 48h down at 50 ℃ in the solution in DMF (2.0mL) and with reaction mixture to triazole.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 5: 1 to 2: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (1: 2 heptane-EA)=0.20 by FC.LC-MS-condition 02:t R=0.77min, [M+H] +=292.24.
2-[2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl methyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-(2-methyl-[1,3] dioxolane-2-yl)-4-(4-nitro-[1,2,3] triazole-2-ylmethyl)-pyridine (145mg, 0.50mmol), iron powder (84mg, 1.49mmol) and NH 4(134mg, 2.49mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 60min down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1N NaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is faint yellow oily to be provided.LC-MS-condition 02:t R=0.54min; [M+H] +=261.78.
2-(4-bromo-thiophene-2-yl)-2-methyl-[1,3] dioxolane:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with trimethyl orthoformate (2.14mL, 19.51mmol), then LiBF 4(150mg 1.60mmol) handles commercially available 1-(4-bromo-2-thienyl) second-1-ketone (2.00g, 9.75mmol) solution in ethylene glycol (10.7mL).Heating is overnight down at 95 ℃ with reaction mixture.Add saturated NaHCO 3The aqueous solution (20mL) and with EA (20mL) extraction mixture.(2 * 20mL) washings are through MgSO with salt solution with organic extract 4Solvent is filtered and under reduced pressure removed to drying.(20: the 80EA-heptane) the purifying resistates provides the title compound of the solid state that is white in color by FC.TLC:rf (20: 80 EA-heptane)=0.50.LC-MS-condition 02:t R=0.99min.
[5-(2-methyl-[1,3] dioxolane-2-yl)-thiene-3-yl-]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, through 15min to 2-(4-bromo-thiophene-2-yl)-(1.00g is 4.01mmol) in Et for 2-methyl-[1,3] dioxolane 2Dropwise add in the solution among the O (36.0mL) n-BuLi (2.5mL, the 1.6M solution in hexane, 4.00mmol).Then, under-78 ℃, reaction mixture is stirred 15min, dropwise add subsequently D MF (3.1mL, 40.14mmol).Remove cooling bath and reaction mixture is stirred 10min.Add saturated NH 4The Cl aqueous solution (40mL) and with EA (2 * 100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered and is under reduced pressure removed solvent so that thick 5-(2-methyl-[1, the 3] dioxolane-2-yl)-thiophene-3-formaldehyde that is yellow oily to be provided.LC-MS-condition 02:t R=0.84min.At inert atmosphere (N 2) under, should thick substance dissolves in MeOH (9.98mL) and under 0 ℃ with NaBH 4(284mg is 7.21mmol) by a part processing.Reaction mixture is at room temperature stirred 2h.Reaction mixture is poured in the water (16mL), and with EA (2 * 100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 50: 50 by FC.TLC:rf (50: the 50EA-heptane)=0.21.LC-MS-condition 02:t R=0.71min; [M+H] +=201.49.
2-(4-chloromethyl-thiophene-2-yl)-2-methyl-[1,3] dioxolane:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.42mL, 2.99mmol), then DMAP (28mg, 0.23mmol) and Ms-Cl (0.21mL 2.76mmol) handles that [5-(2-methyl-[1,3] dioxolane-2-yl)-thiene-3-yl-]-(460mg is 2.30mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (4.6mL).After at room temperature stirring 2h, with water (10mL) stopped reaction mixture, with CH 2Cl 2(20mL) extraction and with the organic extract that merged through the NaSO4 drying, filter, and under reduced pressure remove solvent.(heptane-EA) the purifying resistates provided the title compound that is light yellow oily in 4: 1 by FC.TLC:rf (1: the 4EA-heptane)=0.35.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiene-3-yl-methyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-(4-chloromethyl-thiophene-2-yl)-2-methyl-[1,3] dioxolane (230mg, 1.05mmol) solution in DMF (1.5mL) is added into (0.30mL through DIPEA, 1.75mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (100mg, 0.88mmol) in the solution in DMF (1.5mL), and reaction mixture stirred 16h down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 2: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (2: 1 heptane-EA)=0.47 by FC.LC-MS-condition 02:t R=0.98min.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiene-3-yl-methyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiene-3-yl-methyl]-4-nitro-2H-[1,2,3] triazole (50mg, 0.17mmol), iron powder (29mg, 0.51mmol) and NH 4(46mg, 0.84mmol) mixture in the mixture of EtOH (1.0mL) and water (0.5mL) stirs 15min down at 85 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1N NaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is faint yellow oily to be provided.LC-MS-condition 02:t R=0.78min; [M+H] +=267.28.
5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazoles-3-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (5.00g 26.29mmol) is dissolved among the anhydrous THF (200mL) with commercially available 5-hydroxymethyl-isoxazoles-3-ethyl formate.At room temperature add tertiary butyl dimethylsilyl chlorine (4.04g, 26.82mmol), then add imidazoles (1.97g, 28.92mmol).With reaction mixture stirred overnight at room temperature.Add saturated NH 4The Cl aqueous solution (150mL) then adds EA (100mL) and separates all layers.With EA (2 * 100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 9: 1 heptane-EA) provides the title compound that is faint yellow oily: TLC:rf (9: 1 heptane-EA)=0.37 by FC.LC-MS-condition 02:t R=1.14min; [M+AcCN+H] +=327.51.
[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazole-3-bases]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (40.00mL, the 1M solution in THF 40.43mmol) are handled 5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazoles-3-ethyl formate (5.77g, 20.22mmol) solution in THF (200mL) with DiBAL-H under-78 ℃.Reaction mixture is stirred 1h under this temperature, make it be warming up to room temperature subsequently.Reaction mixture is poured on the Rochelle salt (200mL), and at room temperature stirs 1h.With EA (2 * 200mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(the purifying resistates of 70: 30 heptane-EA) provides the title compound that is yellow oily: TLC:rf (70: 30 heptane-EA)=0.28 by FC.LC-MS-condition 02:t R=0.99min; [M+H] +=244.35.
5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazoles-3-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(8.17g, 84.56mmol) processing [5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazole-3-bases]-methyl alcohol (2.94g, 12.08mmol) solution in AcCN (120.0mL), and reaction mixture at room temperature stirred 24h, pass through diatomite filtration subsequently.Under reduced pressure remove solvent so that the title compound that is yellow oily: TLC:rf to be provided (9: 1 heptane-EA)=0.32.LC-MS-condition 02:t R=0.92min.
1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazole-3-bases]-ethanol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, ((1.74g is 7.22mmol) in CH for-isoxazoles-3-formaldehyde 22.0mmol) to handle 5-(tertiary butyl-dimethyl-silane oxygen ylmethyl) for 22.0mL, the 1M solution in heptane with trimethyl aluminium 2Cl 2Solution (72.0mL).Then, reaction mixture is stirred 50min down at 0 ℃.Then add CH 2Cl 2(80.0mL), add saturated NH subsequently 4The Cl aqueous solution (80mL).Then, with 1N HCl (50mL) treating mixture and with CH 2Cl 2(100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and under reduced pressure removes solvent so that the title compound that is colorless oil: TLC:rf to be provided (7: 3 heptane-EA)=0.32.LC-MS-condition 02:t R=1.01min, [M+H] +=258.41.
1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazole-3-bases]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with MnO 2(3.36g, 34.77mmol) processing 1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazole-3-bases]-ethanol (1.79g, 6.95mmol) solution in AcCN (70.0mL), and reaction mixture at room temperature stirred 72h, pass through diatomite filtration subsequently.Under reduced pressure remove solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=1.13min.
1-(5-hydroxymethyl-isoxazole-3-bases)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (1.71mL 15.58mmol), follows LiBF with trimethyl orthoformate 4(146mg 1.56mmol) handles 1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-isoxazole-3-bases]-ethyl ketone (1.99g, 7.79mmol) solution in ethylene glycol (8.69mL).Heating is overnight down at 95 ℃ with reaction mixture.Add saturated NaHCO 3The aqueous solution (50mL) and with EA (2 * 50mL) extraction mixtures.(2 * 50mL) washings are through MgSO with salt solution with the organic extract that merged 4Solvent is filtered and under reduced pressure removed to drying.(40: the 60EA-heptane) the purifying resistates provides the title compound that is yellow oily by FC.TLC:rf (40: the 60EA-heptane)=0.25.LC-MS-condition 02:t R=0.54min.
1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-isoxazole-3-bases]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.34mL, 2.41mmol), then DMAP (23mg, 0.19mmol) and Ms-Cl (0.17mL, (262mg is 1.86mmol) in anhydrous CH 2.23mmol) to handle 1-(5-hydroxymethyl-isoxazole-3-bases)-ethyl ketone 2Cl 2Solution (2.6mL).After at room temperature stirring 2h, reaction mixture is ended with water (10mL), with CH 2Cl 2(2 * 10mL) extractions, and with the organic extract that merged through the NaSO4 drying, filter, and under reduced pressure remove solvent so that thick 1-(5-chloromethyl-isoxazole-3-base)-ethyl ketone that is light yellow oily to be provided.Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, this thick 1-(5-chloromethyl-the isoxazole-3-bases)-solution of ethyl ketone in DMF (3.0mL) is added into (0.63mL through DIPEA, 3.68mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (210mg, 1.84mmol) in the solution in DMF (3.0mL), and reaction mixture stirred 16h down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 2: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (2: 1 heptane-EA)=0.26 by FC.LC-MS-condition 02:t R=0.90min.
2-[3-(2-methyl-[1,3] dioxolane-2-yl)-isoxazole-5-base methyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with trimethyl orthoformate (0.11mL, 1.03mmol), then LiBF 4(10mg 0.10mmol) handles 1-[5-(4-nitro-[1,2,3] triazole-2-ylmethyl)-isoxazole-3-bases]-ethyl ketone (122mg, 0.51mmol) solution in ethylene glycol (0.57mL).Heating is overnight down at 95 ℃ with reaction mixture.Add saturated NaHCO 3The aqueous solution (10mL) and with EA (2 * 10mL) extraction mixtures.(2 * 10mL) washings are through MgSO with salt solution with the organic extract that merged 4Solvent is filtered and under reduced pressure removed to drying.(40: the 60EA-heptane) the purifying resistates provides the title compound that is yellow oily by FC.TLC:rf (40: the 60EA-heptane)=0.26.LC-MS-condition 02:t R=0.89min.
2-[3-(2-methyl-[1,3] dioxolane-2-yl)-isoxazole-5-base methyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[3-(2-methyl-[1,3] dioxolane-2-yl)-isoxazole-5-base methyl]-4-nitro-2H-[1,2,3] triazole (95mg, 0.34mmol), iron powder (57mg, 1.01mmol) and NH 4(91mg, 1.69mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 15min down at 85 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1N NaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is faint yellow oily to be provided.LC-MS-condition 02:t R=0.66min; [M+H] +=252.34.
5-(3-isopropoxy methyl-phenyl)-oxazoles-4-isopropyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (239mg 5.48mmol) handles 5-(3-hydroxymethyl-phenyl)-oxazoles-4-formic acid (200mg, the 0.912mmol) solution in DMF (2.5mL), and the gained mixture stirred 45min down at 0 ℃ with NaH under 0 ℃.(0.93mL, 9.12mmol) and at room temperature stirred reaction mixture is until finishing to add 2-iodopropane.Add saturated NH 4The Cl aqueous solution (20mL) and with water layer with EA (2 * 20mL) extracting twice.(2 * 10mL) washings are through MgSO with water with the organic layer that merged 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 1: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.45.LC-MS-condition 02:t R=1.05min, [M+H] +=304.28.
5-(3-isopropoxy methyl-phenyl)-oxazoles-4-formic acid:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, handle 5-(3-isopropoxy methyl-phenyl)-oxazoles-4-isopropyl formate (78mg, 0.26mmol) solution in THF (2.5mL) with 1N NaOH (1.3mL).The gained mixture is stirred 1.5h, then with 1N HCl acidifying, with EA (2 * 20mL) extracting twice and the organic phase that is merged with salt solution (20mL) washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.87min, [M+AcCN+H] +=303.18.
5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-isopropyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NaH (112mg 2.57mmol) handles 5-[3-(2-hydroxyl-ethyl)-phenyl]-oxazoles-4-formic acid (200mg, the 0.86mmol) solution in DMF (2.0mL), and the gained mixture stirred 45min down at 0 ℃.Then, (0.44mL, 4.28mmol) and at room temperature stirred reaction mixture is until finishing to add 2-iodopropane.With reaction mixture with saturated NH 4The Cl aqueous solution (20mL) is ended, with EA (2 * 20mL) extractions, and with the organic extract that merged (2 * 20mL) washings are through MgSO with water 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound of the solid state that is white in color in 1: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.49.LC-MS-condition 02:t R=1.06min; [M+H] +=318.36.
(2-bromo-thiazole-5-yl)-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (2.100g 10.94mmol) is dissolved among the MeOH (50mL) with commercially available 2-bromo-thiazole-5-formaldehyde.Add a NaBH by part down at 0 ℃ 4(535mg 13.58mmol) and at room temperature stirs 1h with reaction mixture.Add water (50mL) and with EA (3 * 50mL) extraction mixtures.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is the yellow solid shape to be provided.TLC:rf (1: 1 heptane-EA)=0.31.LC-MS-condition 01:t R=0.56min; [M+AcCN+H] +=234.84.
2-bromo-5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (2.17g 11.18mmol) is dissolved in anhydrous CH with (2-bromo-thiazole-5-yl)-methyl alcohol 2Cl 2(30mL).0 ℃ add down tertiary butyl dimethylsilyl chlorine (1.85g, 12.30mmol), then add imidazoles (1.56g, 22.92mmol).Reaction mixture is at room temperature stirred 16h.Add 10%K 2CO 3The aqueous solution (10mL) separates all layers and with CH 2Cl 2(2 * 20mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(heptane to 10: 1 heptane-EA) the purifying resistates provides the title compound that is yellow oily by FC.TLC:rf (2: 1 heptane-EA)=0.80.LC-MS-condition 02:t R=1.13min; [M+H] +=307.90.
1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiazol-2-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, with 2-bromo-5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-(3.00g is 9.73mmol) in anhydrous Et for thiazole 2Solution among the O (20mL) adds as for Et 2(4.30mL, the 2.5M solution in hexane is 10.70mmol) in the solution for n-BuLi among the O (50mL).Then, reaction mixture is stirred down 40min at-78 ℃, dropwise add subsequently N,N-dimethylacetamide (1.81mL, 19.46mmol).Make reaction mixture be warming up to-50 ℃ and under this temperature, stir 20min.Add saturated NH 4The Cl aqueous solution (20mL) separates all layers, and with Et 2O (3 * 20mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC:rf (1: 2 heptane-EA)=0.80.LC-MS-condition 01:t R=1.09min, [M+H] +=271.98.
[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-yl]-methyl alcohol:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and condenser in flame-dried round-bottomed flask, with trimethyl orthoformate (2.22mL, 20.27mmol), then LiBF 4(190mg 1.99mmol) handles 1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiazol-2-yl]-(2.70g is 9.95mmol) in ethylene glycol (10.68mL, 191.48mmol) solution in for ethyl ketone.Reaction mixture was heated 4 days down at 95 ℃.Add saturated Na 2CO 3The aqueous solution (50mL) and with mixture with Et 2(2 * 50mL) extractions are through MgSO for O 4Solvent is filtered and under reduced pressure removed to drying so that 3.50g 5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole (TLC:rf (1: 1 heptane-EA)=0.41, LC-MS-condition 02:t to be provided R=1.11min, [M+H] +=316.38) and [2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-yl]-methyl alcohol (TLC:rf (1: 1 heptane-EA)=0.13, LC-MS-condition 02:t R=0.61min, [M+H] +=202.47) brown oily mixture.Under 0 ℃, (3.0mL, the 1M solution in THF 3.00mmol) are handled the solution of this mixture in anhydrous THF (15mL) with NAH.Reaction mixture is stirred 5min down and at room temperature stirs 3h at 0 ℃.Then, with EA (10mL) dilution, (3 * 10mL) washings are through MgSO with salt solution with mixture 4Drying is filtered and is under reduced pressure concentrated.(5: 1-＞heptane-EA) the purifying resistates provided the title compound that is yellow oily in 1: 3 by FC.TLC:rf (1: 2 heptane-EA)=0.20.LC-MS-condition 01:t R=0.56min; [M+H] +=201.92.
5-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.50mL, 3.60mmol), then DMAP (34mg, 0.28mmol) and Ms-Cl (0.28mL 3.51mmol) handles that [2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-yl]-(560mg is 2.78mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (5.0mL).After stirring 1h under 0 ℃, reaction mixture is ended with water (10mL), with CH 2Cl 2(10m L) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided the title compound that is light yellow oily in 5: 1 to 2: 1 by FC.TLC:rf (1: 2 heptane-EA)=0.50.LC-MS-condition 01:t R=0.81min; [M+H] +=219.89.
2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 5-chloromethyl-2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole (339mg, 1.54mmol) solution in DMF (2.0mL) is added into (0.48mL through DIPEA, 2.81mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (160mg, 1.40mmol) in the solution in DMF (2.0mL), and reaction mixture stirred 72h down at 50 ℃.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 5: 1 to 2: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (1: 2 heptane-EA)=0.39 by FC.LC-MS-condition 02:t R=0.89min; [M+H] +=298.13.
2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-ylmethyl]-4-nitro-2H-[1,2,3] triazole (201mg, 0.68mmol), iron powder (114mg, 2.03mmol) and NH 4(183mg, 3.38mmol) mixture in the mixture of EtOH (3.0mL) and water (1.5mL) stirs 60min down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1N NaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily: TLC:rf (19: 1CH to be provided 2Cl 2-MeOH)=0.2.LC-MS-condition 02:t R=0.68min; [M+H] +=268.25.
1-oxazole-2-base-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-15 ℃, ((3.25mL, the 48.49mmol) solution in anhydrous THF (34mL) remains on temperature below-10 ℃ simultaneously 48.49mmol) to handle Shi Shou oxazole for 24.2mL, the 2.0M solution in THF with isopropyl-magnesium chloride through 30min.Then, reaction mixture is stirred down 40min at-15 ℃, dropwise make an addition to subsequently N-methoxyl group-N-methylacetamide among the THF (10mL) (4.12mL, 38.79mmol).Make reaction mixture be warming up to room temperature and stirred overnight at room temperature.Add 20%NH 4Cl (150mL) separates all layers, and with Et 2O (3 * 100mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.By FC (4: 6Et 2The O-hexane) the purifying resistates provides and is orange buttery title compound.TLC:rf (4: 6Et 2The O-hexane)=0.27.LC-MS-condition 02:t R=0.47min.
1-oxazole-2-base-ethanol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (446mg 4.01mmol) is dissolved among the MeOH (8.0mL) with 1-oxazole-2-base-ethyl ketone.Add a NaBH by part down at 0 ℃ 4(206mg 5.22mmol) and with reaction mixture at room temperature stirs 30min.Add water (16mL) and with EA (3 * 20mL) extraction mixtures.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is colorless oil to be provided.LC-MS-condition 02:t R=0.33min.
2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (348mg 3.08mmol) is dissolved among the anhydrous THF (15mL) with 1-oxazole-2-base-ethanol.At room temperature add tertiary butyl dimethylsilyl chlorine (580mg, 3.85mmol), then add imidazoles (262mg, 3.85mmol).Reaction mixture is at room temperature stirred 16h.Add saturated NH 4The Cl aqueous solution (20mL) separates all layers, and with EA (2 * 20mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.By FC (1: 4 Et 2The O-hexane) the purifying resistates provides the title compound that is colorless oil.TLC:rf (1: 4 Et 2The O-hexane)=0.39.C-MS-condition 02:t R=1.08min, [M+H] +=228.48.
2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, with tert-butyl lithium (2.62mL, 1.6M solution in pentane, 4.19mmol) processing 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-(733mg, the 3.22mmol) solution in anhydrous THF (16mL) remains on temperature under-70 ℃ oxazole simultaneously.Then, reaction mixture is stirred 1h down at-40 ℃.Under-78 ℃, dropwise add DMF (0.50mL, 6.45mmol).Make reaction mixture be warming up to room temperature and at room temperature stir 2h.Add water (30mL), then add saturated NH 4The Cl aqueous solution (20mL) and EA (20mL) separate all layers and with EA (2 * 30mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Solvent is filtered and under reduced pressure removed to drying.(1: the 4EA-heptane) the purifying resistates provides the title compound that is colorless oil by FC.TLC:rf (1: 4 EA-heptane)=0.33.LC-MS-condition 02:t R=1.08min, [M+H] +=256.38,
2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-yl }-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-(457mg 1.79mmol) is dissolved among the MeOH (8.0mL) oxazole-5-formaldehyde.Under 0 ℃, by a part interpolation NaBH 4(92mg 2.33mmol) and with reaction mixture at room temperature stirs 20min.Add water (16mL) and with EA (3 * 20mL) extraction mixtures.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is colorless oil to be provided.LC-MS-condition 02:t R=0.97min, [M+H] +=258.32.
2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-5-chloromethyl-oxazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.32mL, 2.30mmol), then DMAP (22mg, 0.18mmol) and Ms-Cl (0.17mL 2.12mmol) handles { 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-yl }-(455mg is 1.77mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (4.5mL).After at room temperature stirring 2h, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed the title compound that be light yellow oily (the LC-MS-condition 02:t of solvent so that 2: 1 ratios to be provided R=1.13min, [M+H] +=276.06) and methanesulfonic 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-base methyl esters (LC-MS-condition 02:t R=1.07min, [M+H] +=336.45).
2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-5-chloromethyl-oxazole (247mg, 0.89mmol) solution in DMF (1.0mL) is added into (0.26mL through DIPEA, 1.49mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (850mg, 10% solution in acetone, 0.75mmol) in the solution in DMF (1.0mL), and reaction mixture stirred 48h down at 50 ℃.Add water (20mL), then add EA (20mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 2: 1 by FC.TLC:rf (2: 1 heptane-EA)=0.36.LC-MS-condition 02:t R=1.11min; [M+H] +=354.34.
2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl-4-nitro-2H-[1,2,3] triazole (100mg, 0.28mmol), iron powder (48mg, 0.85mmol) and NH 4(76mg, 1.42mmol) solution in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 20min down at 85 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add water (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through MgSO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=0.98min; [M+H] +=324.42.
5-phenyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with HOBt (40mg, 0.30mmol), EDC (119mg, 0.62mmol), (8mg ,-oxazoles-(47mg is 0.25mmol) in CH for 4-formic acid 0.06mmol) to handle the 5-phenyl for DMAP 2Cl 2Solution (1.5mL), and the gained mixture at room temperature stirred 30min.Then make an addition to CH 2Cl 22-{2-[1-(1.0mL) (tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] (80mg 0.25mmol), and at room temperature stirs 72h with the gained mixture to triazole-4-base amine.Add CH 2Cl 2(20mL), then add water (15mL) and with CH 2Cl 2Aqueous phase extracted.With organic phase Yi Shui, the salt water washing that is merged, through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.LC-MS-condition 02:t R=1.17min, [M+H] +=495.54.
5-phenyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with TBAF (0.48mL, 1M solution in THF, 0.48mmol) processing 5-phenyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides (120mg, 0.24mmol) solution in anhydrous THF (2.1mL).Reaction mixture is stirred 45min down at 0 ℃.Then, mixture is diluted with EA (10mL), with NaHCO 3(3 * 10mL) washings are through MgSO (10mL), to follow salt solution 4Drying is filtered and is under reduced pressure concentrated.By FC (19: 1CH 2Cl 2-MeOH) the purifying resistates provides the foamed title compound that is white in color.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.19。LC-MS-condition 02:t R=0.88min; [M+H] +=381.23.
1-(2-bromo-thiazole-5-yl)-ethanol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, ((1.80g is 9.37mmol) in CH 46mmol) to handle commercially available 2-bromo-thiazole-5-formaldehyde for 46.0mL, the 1M solution in heptane with trimethyl aluminium 2Cl 2Solution (70.0mL).Then, reaction mixture is stirred 45min down at 0 ℃.Then add CH 2Cl 2(100.0mL), add saturated NH subsequently 4The Cl aqueous solution (100mL).Then, with 1N HCl (50mL) treating mixture and with CH 2Cl 2(150mL) aqueous layer extracted.With the organic extract that merged through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC:rf (1: 2 heptane-EA)=0.40.LC-MS-condition 02:t R=0.70min; [M+AcCN+H] +=249.17.
1-(2-bromo-thiazole-5-yl)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with MnO 2(4.53g, (1.95g, the 9.37mmol) solution in AcCN (90.0mL), and reaction mixture at room temperature stirred 16h pass through diatomite filtration subsequently 46.86mmol) to handle 1-(2-bromo-thiazole-5-yl)-ethanol.Under reduced pressure remove solvent so that the title compound that is the yellow solid shape to be provided.LC-MS-condition 02:t R=0.80min.
2-bromo-5-(2-methyl-[1,3] dioxolane-2-yl)-thiazole:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and condenser in flame-dried round-bottomed flask, with trimethyl orthoformate (2.39mL, 21.76mmol), then with LiBF 4(204mg, (2.20g is 10.68mmol) in ethylene glycol (11.46mL, 205.53mmol) solution in 2.14mmol) to handle 1-(2-bromo-thiazole-5-yl)-ethyl ketone.Reaction mixture was heated 2 days down at 95 ℃.Add saturated NaHCO 3The aqueous solution (50mL) and with EA (50mL) extraction mixture.(2 * 50mL) washings are through MgSO with salt solution with organic extract 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 20: 1 to 3: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.80.LC-MS-condition 01:t R=0.84min; [M+H] +=251.85.
5-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-2-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, with 2-bromo-5-(2-methyl-[1,3] dioxolane-2-yl)-(780mg is 3.12mmol) in anhydrous Et for thiazole 2Solution among the O (10mL) adds as for Et 2(1.25mL, the 2.5M solution in hexane is 3.13mmol) in the solution for n-BuLi among the O (10mL).Then, reaction mixture is stirred down 30min at-78 ℃, dropwise add subsequently DMF (0.29mL, 3.78mmol).Make reaction mixture be warming up to-20 ℃ and under this temperature, stir 20min.Add saturated NH 4The Cl aqueous solution (10mL) separates all layers, and with Et 2O (3 * 10mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is yellow oily in 10: 1 to 3: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.50.LC-MS-condition 01:t R=0.78min; [M+H] +=199.93.
[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 5-(2-methyl-[1,3] dioxolane-2-yl)-(555mg 2.79mmol) is dissolved among the MeOH (5mL) thiazole-2-formaldehyde.Add a NaBH by part down at 0 ℃ 4(136mg 3.46mmol) and with reaction mixture at room temperature stirs 1h.Add water (10mL) and with EA (3 * 20mL) extraction mixtures.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC:rf (1: 1 heptane-EA)=0.25.LC-MS-condition 02:t R=0.64min; [M+H] +=202.48.
Methanesulfonic 5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.50mL, 3.60mmol), then DMAP (34mg, 0.28mmol) and Ms-Cl (0.28mL 3.51mmol) handles that [5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl]-(560mg is 2.78mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (5.0mL).After stirring 1h under 0 ℃, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided and is brown buttery title compound in 5: 1 to 2: 1 by FC.LC-MS-condition 01:t R=0.77min; [M+H] +=279.88;
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with methanesulfonic 5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl esters (445mg, 1.59mmol) solution in DMF (3.0mL) is added into (0.54mL through DIPEA, 3.16mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] (180mg 1.58mmol) stirs 72h down at 50 ℃ in the solution in DMF (3.0mL) and with reaction mixture to triazole.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 5: 1 to 2: 1 heptane-EA) provides the title compound that is light yellow oily: TLC:rf (1: 2 heptane-EA)=0.39 by FC.LC-MS-condition 01:t R=0.85min; [M+H] +=297.91.
2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-4-nitro-2H-[1,2,3] triazole (220mg, 0.74mmol), iron powder (125mg, 2.22mmol) and NH 4(200mg, 3.70mmol) mixture in the mixture of EtOH (3.0mL) and water (1.5mL) stirs 60min down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.Add CH 2Cl 2(10mL), then add 1NNaOH (10mL).With CH 2Cl 2(2 * 10mL) aqueous layer extracted, and through Na 2SO 4The dry organic extract that is merged is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily: TLC:rf to be provided (19: 1 CH 2Cl 2-MeOH)=0.2.LC-MS-condition 02:t R=0.66min.
(4-bromo-thiophene-2-yl)-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (3.93g 20.57mmol) is dissolved among the THF (60.0mL) with commercially available 4-bromo-thiophene-2-formaldehyde.Add a NaBH by part down at 0 ℃ 4(892mg 22.63mmol) and with reaction mixture at room temperature stirs 30min.Add saturated NaHCO 3The aqueous solution and with Et 2O extracts mixture.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is colorless oil to be provided.TLC:rf (2: 1 heptane-EA)=0.38.
(4-bromo-thiophene-2-the ylmethoxy)-tertiary butyl-dimethyl-silane:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (3.97g 20.57mmol) is dissolved in anhydrous CH with (4-bromo-thiophene-2-yl)-methyl alcohol 2Cl 2(50mL).At room temperature add tertiary butyl dimethylsilyl chlorine (3.59g, 22.63mmol), then add imidazoles (1.56g, 22.63mmol).Reaction mixture is at room temperature stirred 1h.Add water, separates all layer and through MgSO 4Dry organic layer is filtered, and is under reduced pressure removed solvent.Provide the title compound that is colorless oil by FC (heptane) purifying resistates.TLC:rf (100: 1 heptane-EA)=0.44.LC-MS-condition 02:t R=1.21min.
1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiene-3-yl-]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, (3.07g is 10.00mmol) in anhydrous Et with (4-bromo-thiophene-2-the ylmethoxy)-tertiary butyl-dimethyl-silane 2Solution among the O (10mL) is added into n-Butyl Lithium, and (4.10mL, the 2.5M solution in hexane is 10.25mmol) in Et 2In the solution among the O (40mL), simultaneously temperature is remained on below-70 ℃.Then, under-78 ℃, reaction mixture is stirred 30min.Under-78 ℃, dropwise add N, and N-dimethyl-ethanamide (1.20mL, 12.91mmol).Then, reaction mixture is stirred 1h down at-78 ℃, then at room temperature stir 1h.Add saturated NH 4The Cl aqueous solution separates all layers and with Et 2O (3 * 50mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(0: 100 to 10: the 90EA-heptane) the purifying resistates provides the title compound that is the yellow solid shape by FC.TLC:rf (1: the 9EA-heptane)=0.30.LC-MS-condition 02:t R=1.15min.
The tertiary butyl-dimethyl-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethoxy]-silane:
At inert atmosphere (N 2) under, be equipped with magnetic stirring bar and condenser in flame-dried round-bottomed flask, with trimethyl orthoformate (0.66mL, 6.02mmol), then with LiBF 4(57mg 0.60mmol) handles 1-[5-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-thiene-3-yl-]-(811mg is 3.00mmol) in ethylene glycol (3.5mL, 62.76mmol) solution in for ethyl ketone.Reaction mixture is heated 2h down at 95 ℃.Add saturated Na 2CO 3The aqueous solution (50mL) and with mixture with Et 2(2 * 50mL) extractions are through MgSO for O 4Drying is filtered, and is under reduced pressure removed solvent.(1: the 20EA-heptane) the purifying resistates provides the title compound that is yellow oily by FC.TLC:rf (1: the 10EA-heptane)=0.34.LC-MS-condition 02:t R=1.17min; [M+H] +=315.22.
[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NAH (2.6mL, 1M solution in THF, 2.60mmol) the processing tertiary butyl-dimethyl-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethoxy]-silane (545mg, 1.73mmol) solution in anhydrous THF (5.0mL).Reaction mixture is stirred 2h down at 0 ℃.Then, with EA (10mL) dilution, (3 * 20mL) washings are through MgSO with salt solution with mixture 4Drying is filtered and is under reduced pressure concentrated.(1: the 5EA-heptane) the purifying resistates provides the title compound that is colorless oil by FC.TLC:rf (1: the 1EA-heptane)=0.36.LC-MS-condition 02:t R=0.70min.
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.23mL, 1.64mmol), then with DMAP (16mg, 0.13mmol) and Ms-Cl (0.12mL 1.55mmol) handles that [4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-yl]-(256mg is 1.28mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (5.0mL).After stirring 30min under 0 ℃ and at room temperature stirring 1h, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that thick 2-(5-chloromethyl-thiene-3-yl-)-2-methyl-[1,3] dioxolane (TLC:rf (1: the 1EA-heptane)=0.61) to be provided.At room temperature, with through DIPEA (0.40mL, 2.34mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] triazole (124mg, 1.07mmol) solution of the thick material of solution-treated in DMF (3mL) in DMF (2.0mL).The gained mixture was at room temperature stirred for 2 weeks.Add water (10mL), then add EA (10mL).Organic extract is washed with water (10mL), through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane to 1: the purifying resistates of 1 heptane-EA) provides the title compound that is yellow oily: TLC:rf (1: 1 heptane-EA)=0.48 by FC.
2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 1-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-4-nitro-1H-pyrazoles (115mg, 0.39mmol), iron powder (65mg, 1.16mmol) and NH 4(106mg, 1.97mmol) mixture in the mixture of EtOH (3.0mL) and water (1.5mL) stirs 60min down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.With filtrate through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily: TLC:rf to be provided (EA)=0.63.LC-MS-condition 02:t R=0.76min; [M+H] +=267.09.
(E)-2-styryl-oxazoles-4-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 3-bromo-2-oxygen-ethyl propionate (13.04mL, 88.33mmol) handle 3-phenyl-acrylamide (10.31g, 67.95mmol) and NaHCO 3(28.47g, the 339.73mmol) suspension in THF (260mL), and reaction mixture heated 15h under refluxing.(13.04mL 88.33mmol) and with reaction mixture stirs 15h under refluxing to add 3-bromo-2-oxygen-ethyl propionate once more.Then, through diatomite filtration reaction mixture and vapourisation under reduced pressure solvent.Be dissolved in resistates among the THF (30mL) and (30.0mL 215.83mmol) dropwise handles with trifluoroacetic anhydride under 0 ℃.Then, with reaction mixture stirred overnight at room temperature.Add saturated Na 2CO 3The aqueous solution and with mixture with EA (3 * 150mL) extraction, through MgSO 4Drying is filtered, and is under reduced pressure removed solvent.(1: the 9EA-heptane) the purifying resistates provides the title compound that is the yellow solid shape by FC.TLC:rf (1: the 9EA-heptane)=0.1.LC-MS-condition 02:t R=1.01min; [M+H] +=244.48.
2-formyl radical-oxazoles-4-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (3.21g, 15.00mmol) solution in water (26.0mL) slowly is added in the suspension of silica gel (15.0g) in acetone (60.0mL) through vigorous stirring with NaIO4.Then, enriched mixture and make blocks of solid under reduced pressure at CH 2Cl 2Middle pulp, and vapourisation under reduced pressure solvent.Add CH 2Cl 2(40.0mL), and at room temperature with (E)-2-styryl-oxazoles-4-ethyl formate (1.22g, 5.00mmol) and RuCl 3Hydrate (82mg, 0.15mmol) reaction mixture.Reaction mixture is at room temperature stirred 30min in the dark, filtered and under reduced pressure concentrate.(1: 9 to 1: the 2EA-heptane) the purifying resistates provides the title compound that is the yellow solid shape by FC.TLC:rf (3: the 2EA-heptane)=0.21.LC-MS-condition 02:t R=0.51min; [M+H 2O+H] +=188.50.
2-hydroxymethyl-oxazolidin-4-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (272mg 1.61mmol) is dissolved among the EtOH (5.0mL) with 2-formyl radical-oxazoles-4-ethyl formate.Add a NaBH by part down at 0 ℃ 4(112mg 2.84mmol) and with reaction mixture stirs 1h down at 0 ℃.Add saturated NH 4The Cl aqueous solution and with EA (5 * 10mL) extraction mixtures.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC：rf(EA)＝0.50。LC-MS-condition 02:t R=0.58min; [M+H] +=172.03.
2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ethyl formate:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, (275mg 1.61mmol) is dissolved in anhydrous CH with 2-hydroxymethyl-oxazolidin-4-ethyl formate 2Cl 2(5.0mL).At room temperature add tertiary butyl dimethylsilyl chlorine (510mg, 3.22mmol), then add imidazoles (221mg, 3.22mmol).Reaction mixture is at room temperature stirred 30min.Add water, separates all layer and through Na 2SO 4Dry organic layer is filtered, and is under reduced pressure removed solvent.(1: 20 to 1: the 9EA-heptane) the purifying resistates provides the title compound that is colorless oil by FC.TLC:rf (9: 1 heptane-EA)=0.15.LC-MS-condition 02:t R=1.10min; [M+H] w=286.38.
2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-formaldehyde:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-78 ℃, ((283mg is 0.99mmol) in CH for-oxazoles-4-ethyl formate 1.85mmol) to handle 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl) for 1.85mL, the 1M solution in toluene with DiBAL 2Cl 2Solution (5.0mL), and with reaction mixture stirring 1h under-78 ℃.Add MeOH (70 μ L) and H 2O (100 μ L) and make reaction mixture be warming up to room temperature.Reaction mixture is filtered, and under reduced pressure remove solvent so that the title compound that is colorless oil to be provided.TLC:rf (1: 1 heptane-EA)=0.61.LC-MS-condition 02:t R=1.03min; [M+H 2O+H] +=260.50.
1-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-yl]-ethanol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, ((223mg is 0.92mmol) in CH for-oxazoles-4-formaldehyde 5.00mmol) to handle 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl) for 2.50mL, the 2M solution in toluene with trimethyl aluminium 2Cl 2Solution (8.0mL).Then, reaction mixture is stirred 45min down at 0 ℃.Then add saturated NH 4The Cl aqueous solution and with water layer with CH 2Cl 2Extracting twice and with the EA extracting twice.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is colorless oil to be provided.TLC:rf (1: 1 heptane-EA)=0.32.LC-MS-condition 02:t R=0.97min, [M+H] +=258.30.
1-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(362mg 3.75mmol) handles 1-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-yl]-ethanol (193mg, 0.75mmol) solution in AcCN (5.0mL).Reaction mixture is at room temperature stirred 16h, pass through diatomite filtration subsequently.Under reduced pressure remove solvent so that the title compound of the solid state that is white in color to be provided.TLC:rf (1: 1 heptane-EA)=0.69.LC-MS-condition 02:t R=1.04min, [M+H] +=255.84.
1-(2-hydroxymethyl-oxazolidin-4-yl)-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with NAH (1.1mL, the 1M solution in THF 1.10mmol) are handled 1-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-yl]-ethyl ketone (192mg, 0.75mmol) solution in anhydrous THF (5.0mL).Reaction mixture is at room temperature stirred 1.5h.Then, with EA (10mL) dilution, (3 * 10mL) washings are through Na with salt solution with mixture 2SO 4Drying is filtered and is under reduced pressure concentrated.Provide the title compound that is the light yellow solid shape by FC (1: 1 to 2: 1 EA-heptane) purifying resistates.TLC：rf(E?A)＝0.37。LC-MS-condition 02:t R=0.34min, [M+H] +=142.46.
Methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.10mL, 0.71mmol), then with DMAP (6mg, 0.05mmol) and Ms-Cl (0.05mL, (75mg is 0.53mmol) in anhydrous CH 0.66mmol) to handle 1-(2-hydroxymethyl-oxazolidin-4-yl)-ethyl ketone 2Cl 2Solution (5.0mL).After stirring 30min under 0 ℃, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC：rf(EA)＝0.63。LC-MS-condition 02:t R=0.64min; [M+H] +=220.22.
1-[2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-oxazoles-4-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under; with methanesulfonic 4-ethanoyl-oxazoles-2-base methyl esters (116mg; 0.53mmol) solution in DMF (3.0mL) is added into (0.20mL through DIPEA; 1.17mmol) 4-nitro-2H-[1 of pre-treatment 30min; 2; 3] (62mg 0.53mmol) in the solution in DMF (2.0mL), and stirs down 20h with reaction mixture at 50 ℃ to triazole.Add water (10mL), then add EA (10mL).With EA (10m L) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(heptane-EA) the purifying resistates provided the title compound that is the yellow solid shape in 3: 1 to 1: 1 by FC.TLC:rf (1: 2 heptane-EA)=0.49.LC-MS-condition 01:t R=0.76min.
1-[2-(4-amino-[1,2,3] triazole-2-ylmethyl)-oxazoles-4-yl]-ethyl ketone:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with 1-[2-(4-nitro-[1,2,3] triazole-2-ylmethyl)-oxazoles-4-yl]-ethyl ketone (48mg, 0.20mmol), iron powder (34mg, 0.61mmol) and NH 4(54mg, 1.01mmol) mixture in the mixture of EtOH (2.0mL) and water (1.0mL) stirs 60min down at 75 ℃ to Cl.Filtered while hot reaction mixture and under reduced pressure concentrated.With filtrate through Na 2SO 4Drying is filtered, and under reduced pressure removes solvent and be brown buttery title compound to provide.TLC：rf(EA)＝0.40。LC-MS-condition 02:t R=0.54min; [M+H] +=208.44.
5-(3-fluoro-phenyl)-2-methyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with HOBt (25mg, 0.19mmol), EDC (74mg, 0.38mmol), (5mg 0.04mmol) handles that 5-(3-fluoro-phenyl)-(34mg is 0.16mmol) in CH for 2-methyl-oxazoles-4-formic acid to DMAP 2Cl 2Solution (1.0mL), and the gained mixture at room temperature stirred 30min.Then make an addition to CH 2Cl 22-{2-[1-(0.6mL) (tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] (50mg 0.16mmol), and at room temperature stirs 16h with the gained mixture to triazole-4-base amine.Add CH 2Cl 2(20mL), then add water (15mL) and with CH 2Cl 2Aqueous phase extracted.With organic phase Yi Shui, the salt water washing that is merged, through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be brown buttery title compound to provide.LC-MS-condition 02:t R=1.22min, [M+H] +=527.5.
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NAH (0.42mL, 1M solution in THF, 0.42mmol) processing 5-(3-fluoro-phenyl)-2-methyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides (110mg, 0.21mmol) solution in anhydrous THF (2.1mL).Reaction mixture is stirred 45min down at 0 ℃.Then, mixture is diluted with EA (10mL), with NaHCO 3(3 * 10mL) washings are through MgSO (10mL), to follow salt solution 4Drying is filtered and is under reduced pressure concentrated.By FC (19: 1CH 2Cl 2-MeOH) the purifying resistates provides and is orange buttery title compound.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.21。LC-MS-condition 02:t R=0.94min; [M+H] +=412.86.
Between 2-methyl-5--tolyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with HOBt (25mg, 0.19mmol), EDC (74mg, 0.38mmol), (5mg 0.04mmol) handles between 2-methyl-5--(34mg is 0.16mmol) in CH for tolyl-oxazoles-4-formic acid DMAP 2Cl 2Solution (1.0mL), and the gained mixture at room temperature stirred 30min.Then make an addition to CH 2Cl 22-{2-[1-(0.6mL) (tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] (50mg 0.16mmol), and at room temperature stirs 16h with the gained mixture to triazole-4-base amine.Add CH 2Cl 2(20mL), then add water (15mL) and with CH 2Cl 2Aqueous phase extracted.With organic phase Yi Shui, the salt water washing that is merged, through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be brown buttery title compound to provide.LC-MS-condition 02:t R=1.23min, [M+H] +=523.56.
Between 2-methyl-5--tolyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NAH (0.41mL, 1M solution in THF, 0.41mmol) handle between 2-methyl-5--tolyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides (109mg, 0.21mmol) solution in anhydrous THF (2.0mL).Reaction mixture is stirred 45min down at 0 ℃.Then, mixture is diluted with EA (10mL), with NaHCO 3(3 * 10mL) washings are through MgSO (10mL), to follow salt solution 4Drying is filtered and is under reduced pressure concentrated.By FC (19: 1CH 2Cl 2-MeOH) the purifying resistates provides the title compound that is yellow oily.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.23。LC-MS-condition 02:t R=0.95min; [M+H] +=409.78.
5-(3-chloro-phenyl)-2-methyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with HOBt (25mg, 0.19mmol), EDC (74mg, 0.38mmol), (5mg 0.04mmol) handles that 5-(3-chloro-phenyl)-(37mg is 0.16mmol) in CH for 2-methyl-oxazoles-4-formic acid to DMAP 2Cl 2Solution (1.0mL), and the gained mixture at room temperature stirred 30min.Then make an addition to CH 2Cl 22-{2-[1-(0.6mL) (tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] (50mg 0.16mmol), and at room temperature stirs 16h with the gained mixture to triazole-4-base amine.Add CH 2Cl 2(20mL), then add water (15mL) and with CH 2Cl 2Aqueous phase extracted.With organic phase Yi Shui, the salt water washing that is merged, through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be brown buttery title compound to provide.LC-MS-condition 02:t R=1.24min, [M+H] +=542.92.
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NAH (0.39m L, 1M solution in THF, 0.39mmol) processing 5-(3-chloro-phenyl)-2-methyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides (106mg, 0.20mmol) solution in anhydrous THF (1.9mL).Reaction mixture is stirred 45min down at 0 ℃.Then, mixture is diluted with EA (10mL), with NaHCO 3(3 * 10mL) washings are through MgSO (10mL), to follow salt solution 4Drying is filtered and is under reduced pressure concentrated.By FC (19: 1 CH 2Cl 2-MeOH) the purifying resistates provides the title compound of the solid state that is white in color.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.22。LC-MS-condition 01:t R=0.93min; [M+H] +=428.97.
Between 5--tolyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with HOBt (25mg, 0.19mmol), EDC (74mg, 0.38mmol), (5mg 0.04mmol) handles between 5--(31mg is 0.16mmol) in CH for tolyl-oxazoles-4-formic acid DMAP 2Cl 2Solution (1.0mL), and the gained mixture at room temperature stirred 30min.Then make an addition to CH 2Cl 22-{2-[1-(0.6mL) (tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] (50mg 0.16mmol), and at room temperature stirs 16h with the gained mixture to triazole-4-base amine.Add CH 2Cl 2(20mL), then add water (15mL) and with CH 2Cl 2Aqueous phase extracted.With organic phase Yi Shui, the salt water washing that is merged, through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be brown buttery title compound to provide.LC-MS-condition 02:t R=1.20min, [M+H] +=509.55.
Between 5--tolyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NAH (0.39mL, 1M solution in THF, 0.39mmol) handle between 5--tolyl-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides (100mg, 0.20mmol) solution in anhydrous THF (1.9mL).Reaction mixture is stirred 45min down at 0 ℃.Then, mixture is diluted with EA (10mL), with NaHCO 3(3 * 10mL) washings are through MgSO (10mL), to follow salt solution 4Drying is filtered and is under reduced pressure concentrated.By FC (19: 1 CH 2Cl 2-MeOH) the purifying resistates provides the title compound that is yellow oily.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.21。LC-MS-condition 02:t R=0.92min; [M+H] +=395.35.
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature, with HOBt (25mg, 0.19mmol), EDC (74mg, 0.38mmol), (5mg ,-oxazoles-(44mg is 0.16mmol) in CH for 4-formic acid 0.04mmol) to handle 2-methyl-5-(3-trifluoromethoxy-phenyl) for DMAP 2Cl 2Solution (1.0mL), and the gained mixture at room temperature stirred 30min.Then make an addition to CH 2Cl 22-{2-[1-(0.6mL) (tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] (50mg 0.16mmol), and at room temperature stirs 16h with the gained mixture to triazole-4-base amine.Add CH 2Cl 2(20mL), then add water (15mL) and with CH 2Cl 2Aqueous phase extracted.With organic phase Yi Shui, the salt water washing that is merged, through MgSO 4Drying is filtered, and under reduced pressure removes solvent and be brown buttery title compound to provide.LC-MS-condition 02:t R=1.25min, [M+H] +=593.58.
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with NAH (0.41mL, 1M solution in THF, 0.41mmol) processing 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-formic acid (2-{2-[1-(tertiary butyl-dimethyl-silicon alkoxyl group)-ethyl]-oxazole-5-ylmethyl }-2H-[1,2,3] triazole-4-yl)-acid amides (122mg, 0.21mmol) solution in anhydrous THF (2.0mL).Reaction mixture is stirred 45min down at 0 ℃.Then, mixture is diluted with EA (10mL), with NaHCO 3(3 * 10mL) washings are through MgSO (10mL), to follow salt solution 4Drying is filtered and is under reduced pressure concentrated.By FC (19: 1CH 2Cl 2-MeOH) the purifying resistates provides the title compound of the solid state that is white in color.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.26。LC-MS-condition 02:t R=1.01min; [M+H] +=479.03.
[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-yl]-methyl alcohol:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with DiBAL (11.6mL, 1M solution in toluene, 11.6mmol) processing 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ethyl formate (830mg, the 2.91mmol) solution in THF (15.0mL), and with reaction mixture stirring 45min under 0 ℃.Then, with EA (5.0mL) diluted reaction mixture, add saturated Rochelle's salt solution (20.0mL) and mixture is at room temperature stirred 2h.Separate all layers and with EA (3 * 20mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is the yellow solid shape to be provided.TLC：rf(EA)＝0.59。LC-MS-condition 02:t R=0.94min; [M+H] +=244.46.
Methanesulfonic 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-base methyl esters:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃, with Et 3N (0.37mL, 2.65mmol), then with DMAP (25mg, 0.20mmol) and Ms-Cl (0.20mL 2.54mmol) handles that [2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-yl]-(500mg is 2.05mmol) in anhydrous CH for methyl alcohol 2Cl 2Solution (10.0mL).After stirring 30min under 0 ℃, reaction mixture is ended with water (10mL), with CH 2Cl 2(10mL) extraction, and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC:rf (1: 1 heptane-EA)=0.50.LC-MS-condition 02:t R=1.05min; [M+H] +=322.25.
2-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ylmethyl]-4-nitro-2H-[1,2,3] triazole:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, with methanesulfonic 2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-base methyl esters (651mg, 2.02mmol) solution in DMF (3.0mL) is added into (0.63mL through DIPEA, 3.68mmol) 4-nitro-2H-[1 of pre-treatment 30min, 2,3] (210mg 1.84mmol) stirs 20h down at 50 ℃ in the solution in DMF (3.0mL) and with reaction mixture to triazole.Add water (10mL), then add EA (10mL).With EA (10mL) aqueous layer extracted and with the organic extract that merged through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent.(the purifying resistates of 5: 1 to 2: 1 heptane-EA) provides the title compound that is yellow oily: TLC:rf (1: 2 heptane-EA)=0.30 by FC.LC-MS-condition 02:t R=1.10min; [M+H] +=340.47.
2-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ylmethyl]-2H-[1,2,3] triazole-4-base amine:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 75 ℃ with 2-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ylmethyl]-4-nitro-2H-[1,2,3] triazole (103mg, 0.30mmol), iron powder (51mg, 0.91mmol) and NH 4Cl (82mg, 1.52mmol) the solution stirring 90min in the mixture of EtOH (3.0mL) and water (1.5mL).Filtered while hot reaction mixture and under reduced pressure concentrated.Resistates is dissolved in CH again 2Cl 2(20mL), through Na 2SO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is yellow oily to be provided.TLC：rf(19∶1?CH 2Cl 2-MeOH)＝0.20。LC-MS-condition 02:t R=0.96min; [M+H] +=310.46.
2-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ylmethyl]-2H-[1,2,3] triazole-4-yl }-carboxylamine 2-chloro-benzyl ester:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃ with DIPEA (0.08mL, 0.48mmol), then with chloroformic acid 2-benzyl chloride ester (0.06mL 0.39mmol) handles 2-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ylmethyl]-2H-[1,2,3] triazole-(93mg is 0.30mmol) in CH for 4-base amine 2Cl 2Solution (5.0mL).Reaction mixture is stirred 1h down and adds water (5.0mL) at 0 ℃.Separate all layers and with CH 2Cl 2(2 * 10mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.(heptane-EA) the purifying resistates provided the title compound that is the orange solids shape in 9: 1 to 1: 1 by FC.TLC:rf (1: 1 heptane-EA)=0.27.LC-MS-condition 01:t R=1.11min; [M+H] +=478.01.
[2-(2-hydroxymethyl-oxazolidin-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under 0 ℃ with TBAF (0.46mL, 1M solution in THF, 0.46mmol) handle 2-[2-(tertiary butyl-dimethyl-silane oxygen ylmethyl)-oxazoles-4-ylmethyl]-2H-[1,2,3] triazole-4-yl }-carboxylamine 2-chloro-benzyl ester (144mg, 0.30mmol) solution in anhydrous THF (3.0mL).Reaction mixture is stirred 30min down at 0 ℃.Add saturated NH 4The Cl aqueous solution (5mL) separates all layers, and with EA (3 * 10mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Drying is filtered and is under reduced pressure concentrated.Provide the title compound that is yellow oily by FC (EA) purifying resistates.TLC：rf(EA)＝0.25。LC-MS-condition 01:t R=0.82min; [M+H] +=363.90.
[2-(2-dihydroxyl methyl-oxazoles-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(49mg 0.51mmol) handles [2-(2-hydroxymethyl-oxazolidin-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester (37mg, 0.10mmol) solution in AcCN (3.0mL), and reaction mixture at room temperature stirred 16h, pass through diatomite filtration subsequently.Under reduced pressure remove solvent so that the title compound that is the brown solid shape to be provided.TLC：rf(EA)＝0.48。LC-MS-condition 02:t R=0.83min; [M+H] +=380.69.
2-[2-(1-hydroxyl-ethyl)-oxazoles-4-ylmethyl]-2H-[1,2,3] triazole-4-yl }-carboxylamine 2-chloro-benzyl ester:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, under-65 ℃ with methylmagnesium-bromide (0.15mL, the 1M solution in THF, 0.15mmol) processing [2-(2-dihydroxyl methyl-oxazoles-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester (19mg, 0.05mmol) solution in THF (1.0mL).Then, reaction mixture is stirred 1h down at-65 ℃.Then, make reaction mixture slowly be warming up to room temperature and under this temperature, stir 45min.Then add saturated NH 4The Cl aqueous solution and with EA (3 * 10mL) aqueous layer extracted.With the organic extract that merged through Na 2SO 4Solvent is filtered and under reduced pressure removed to drying.By FC (EA) purifying resistates so that the title compound that is yellow oily to be provided.TLC：rf(EA)＝0.30。LC-MS-condition 02:t R=0.89min, [M+H] +=378.30.
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid:
Begin to prepare from 3-(3-methoxyl group-phenyl)-3-oxygen-ethyl propionate according to universal program F, G and E successively.LC-MS-condition 02:t R=0.82min; [M+H] +=234.10.
5-(3,5-dimethyl-phenyl)-2-methyl-oxazoles-4-formic acid:
Begin to prepare from 3-(3,5-dimethyl-phenyl)-3-oxygen-ethyl propionate according to universal program F, G and E successively.LC-MS-condition 02:t R=0.89min; [M+H] +=232.12.
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid:
Begin to prepare from 3-(3-fluoro-phenyl)-3-oxygen-ethyl propionate according to universal program F, G and E successively.LC-MS-condition 02:t R=0.83min; [M+H] +=222.14.
Between 2-methyl-5--tolyl-oxazoles-4-formic acid:
Successively according to universal program F, G and E between 3-oxygen-3--tolyl-ethyl propionate begins to prepare.LC-MS-condition 02:t R=0.85min; [M+H] +=218.46.
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid:
Begin to prepare from 3-chloro-phenylformic acid according to universal program K, F, G and E successively.LC-MS-condition 02:t R=0.87min; [M+H] +=238.06.
2-methyl-5-phenyl-oxazoles-4-formic acid:
Begin to prepare from 3-oxygen-3-phenyl-ethyl propionate according to universal program F, G and E successively.LC-MS-condition 02:t R=0.76min; [M+H] +=204.03.
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-trifluoromethyl-phenylformic acid according to universal program K, F, G and E successively.LC-MS-condition 02:t R=0.91min; [M+H] +=272.05.
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-trifluoromethoxy-phenylformic acid according to universal program K, F, G and E successively.LC-MS-condition 02:t R=0.93min; [M+H] +=288.06.
2-methyl-5-neighbour-tolyl-oxazoles-4-formic acid:
Begin to prepare from 3-oxygen-3-neighbour-tolyl-ethyl propionate according to universal program F, G and E successively.LC-MS-condition 02:t R=0.83min; [M+H] +=218.16.
5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-trifluoromethyl-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.89min; [M+AcCN+H] +=298.92.
5-(4-chloro-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 4-chloro-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.85min; [M+AcCN+H] +=264.87.
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-trifluoromethoxy-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.91min; [M+AcCN+H] +=314.98.
5-(3-methoxyl group-4-methyl-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-methoxyl group-4-methyl-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.86min; [M+H] +=234.11.
5-(4-fluoro-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 4-fluoro-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.80min; [M+AcCN+H] +=249.04.
Between 5--tolyl-oxazoles-4-formic acid:
Successively according to universal program J, I, H and E between 3-oxygen-3--tolyl-ethyl propionate begins to prepare.LC-MS-condition 02:t R=0.83min; [M+H] +=204.17.
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-(3-methoxyl group-phenyl)-3-oxygen-ethyl propionate according to universal program J, I, H and E successively.LC-MS-condition 02:t R=0.80min; [M+H] +=220.13.
2-ethyl-5-phenyl-oxazoles-4-formic acid:
Begin to prepare from 3-oxygen-3-phenyl-ethyl propionate according to universal program J, I, H and E successively.LC-MS-condition 02:t R=0.85min; [M+H] +=218.19.
2-cyclopropyl-5-phenyl-oxazoles-4-formic acid:
Begin to prepare from 3-oxygen-3-phenyl-ethyl propionate according to universal program J, I, H and E successively.LC-MS-condition 02:t R=0.87min; [M+H] +=230.17.
5-(3-fluoro-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-fluoro-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.80min; [M+AcCN+H] +=249.09.
5-(3-chloro-phenyl)-oxazoles-4-formic acid:
Begin to prepare from 3-chloro-phenylformic acid according to universal program K, J, I, H and E successively.LC-MS-condition 02:t R=0.85min; [M+AcCN+H] +=265.23.
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid:
Successively according to universal program M and E by the initial preparation of 3-dimethylamino-phenylformic acid.LC-MS-condition 02:t R=0.60min; [M+H] +=233.36.
5-[3-(2-hydroxyl-ethyl)-phenyl]-oxazoles-4-formic acid:
Begin to prepare from 3-(2-hydroxyl-ethyl)-phenylformic acid according to universal program M and E successively.LC-MS-condition 02:t R=0.71min; [M+H] +=234.36.
5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-formic acid:
According to universal program E from 5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-methyl-formiate begins to prepare.LC-MS-condition 02:t R=0.81min; [M+H] +=248.37.
Between 2-methyl-5--tolyl-thiazole-4-formic acid:
Begin to prepare from 3-methyl-phenyl aldehyde according to universal program R, S and E successively.LC-MS-condition 01:t R=0.83min; [M+H] +=234.01.
5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-formic acid:
According to universal program E from 5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-isopropyl formate begins to prepare.LC-MS-condition 02:t R=0.89min; [M+H] +=275.6.
5-(3-fluoro-phenyl)-thiazole-4-formic acid:
Begin to prepare from 3-fluoro-phenyl aldehyde according to universal program R, T, U, V and E successively.LC-MS-condition 01:t R=0.81min; [M+H] +=224.38.
2-methoxymethyl-5-phenyl-oxazoles-4-formic acid:
X, Y and Z according to universal program W, use methoxyacetic acid begins to prepare from DL-3-phenyl silk amino acid hydrate successively.LC-MS-condition 02:t R=0.81min; [M+H] +=234.45.
2-(2-methoxyl group-ethyl)-5-phenyl-oxazoles-4-formic acid:
X, Y and Z according to universal program W, use 3-methoxyl group-propionic acid begins to prepare from DL-3-phenyl silk amino acid hydrate successively.LC-MS-condition 01:t R=0.77min; [M+H] +=247.96.
2-butyl-5-phenyl-oxazoles-4-formic acid:
X, Y and Z according to universal program W, use valeric acid begins to prepare from DL-3-phenyl silk amino acid hydrate successively.LC-MS-condition 02:t R=0.95min; [M+H] +=246.45.
2-sec.-propyl-5-phenyl-oxazoles-4-formic acid:
Successively according to universal program W, use isobutyric X, Y and Z to begin to prepare from DL-3-phenyl silk amino acid hydrate.LC-MS-condition 02:t R=0.90min; [M+H] +=232.51.
2-benzyl-5-phenyl-oxazoles-4-formic acid:
X, Y and Z according to universal program W, use phenyl-acetic acid begins to prepare from DL-3-phenyl silk amino acid hydrate successively.LC-MS-condition 02:t R=0.95min; [M+H] +=220.18.
2-(2-tert-butoxycarbonyl-ethyl)-5-phenyl-oxazoles-4-formic acid:
X, Y and Z according to universal program W, the use Succinic Acid list tert-butyl ester begins to prepare from DL-3-phenyl silk amino acid hydrate successively.LC-MS-condition 02:t R=0.95min; [M+H] +=318.32.
5-(6-trifluoromethyl-pyridine-2-yl)-oxazole-4-formic acid lithium salts:
Begin to prepare from 6-trifluoromethyl-pyridine-2-formic acid according to universal program M and E (using LiOH) successively.LC-MS-condition 02:t R=0.80min; [M+H] +=259.12.
The preparation of example
Example 1:
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B or C, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.99min; [M+H] +=377.99.
Example 2:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide:
According to universal program A, continue with B or C, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(4-trifluoromethyl-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 02:t R=1.03min; [M+H] +=404.99.
Example 3:
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B or C, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.03min; [M+H] +=421.98.
Example 4:
[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D, continue with B or C, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (2-chloro-phenyl)-methyl alcohol begins to prepare.
LC-MS-condition 02:t R=1.00min; [M+H] +=374.97.
Example 5:
5-phenyl-oxazoles-4-formic acid [2-(5-oxygen-hexyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-butyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.99min; [M+H] +=354.36.
Example 6:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-chloro-phenyl)-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(4-chloro-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.7min; [M+H] +=371.11.
Example 7:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(2-trifluoromethyl-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.71min; [M+H] +=405.19.
Example 8:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(3-trifluoromethoxy-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.74min; [M+H] +=421.12.
Example 9:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-neighbour-tolyl-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-neighbour-tolyl-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.67min; [M+H] +=351.18.
Example 10:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-chloro-4-fluoro-phenyl)-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(2-chloro-4-fluoro-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.7min; [M+H] +=389.14.
Example 11:
(E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-between-tolyl-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] between triazole-4-base amine and (E)-3--tolyl-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.68min; [M+H] +=351.22.
Example 12:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-is right-tolyl-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-is right-and tolyl-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.68min; [M+H] +=351.22.
Example 13:
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-methoxyl group-phenyl)-acrylamide:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(4-methoxyl group-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05b:t R=0.62min; [M+H] +=367.18.
Example 14:
5-(3,5-dimethyl-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3,5-dimethyl-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.83min; [M+H] +=420.21.
Example 15:
5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.77min; [M+H] +=446.17.
Example 16:
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.75min; [M+H] +=410.17.
Example 17:
5-(4-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(4-chloro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.76min; [M+H] +=412.13.
Example 18:
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(-tolyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.78min; [M+H] +=406.18.
Example 19:
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.79min; [M+H] +=462.1.
Example 20:
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.80min; [M+H] +=426.14.
Example 21:
5-(3-methoxyl group-4-methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-4-methyl-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.77min; [M+H] +=422.19.
Example 22:
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(4-fluoro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.70min; [M+H] +=396.18.
Example 23:
Between 5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(-tolyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.73min; [M+H] +=392.19.
Example 24:
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.69min; [M+H] +=408.22.
Example 25:
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.73min; [M+H] +=392.18.
Example 26:
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-trifluoromethyl-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.81min; [M+H] +=460.16.
Example 27:
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-trifluoromethoxy-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.83min; [M+H] +=476.12.
Example 28:
2-methyl-5-neighbour-tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(neighbour-tolyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.72min; [M+H] +=406.2.
Example 29:
2-ethyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-ethyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.80min; [M+H] +=406.19.
Example 30:
2-cyclopropyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-cyclopropyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.81min; [M+H] +=417.69.
Example 31:
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluoro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05b:t R=0.71min; [M+H] +=396.19.
Example 32:
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02b:t R=1.04min; [M+H] +=411.88.
Example 33:
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.03min; [M+H] +=394.18.
Example 34:
5-phenyl-oxazoles-4-formic acid [2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.04min; [M+H] +=388.29.
Example 35:
[2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D (step 2), continue with B, from 2-[3-(2-methyl-[1,3] dioxolane-2-yl)-benzyl]-2H-[1,2,3] triazole-4-base amine and chloroformic acid 2-benzyl chloride ester begin to prepare.
LC-MS-condition 01:t R=1.00min; [M+H] +=384.95.
Example 36:
5-phenyl-oxazole-4-formic acid [2-(5,5-two fluoro-hexyls)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, from 2-(5,5-two fluoro-hexyls)-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazole-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.09min; [M+H] +=376.26.
Example 37:
5-phenyl-oxazoles-4-formic acid [2-(5-methane sulfonyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, from 2-(5-methane sulfonyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.97min; [M+H] +=413.84.
Example 38:
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.84min; [M+H] +=421.37.
Example 39:
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.98min; [M+H] +=395.0.
Example 40:
[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D (step 2), continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-benzyl chloride base-chloro-formic ester begin to prepare.
LC-MS-condition 02:t R=0.99min; [M+H] +=391.9.
Example 41:
[2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D (step 2), continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-benzyl chloride base-chloro-formic ester begin to prepare.
LC-MS-condition 02:t R=0.99min; [M+H] +=386.3.
Example 42:
5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.00min; [M+H 2O+H] +=454.30.
Example 43:
5-phenyl-oxazoles-4-formic acid [2-(6-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[6-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 01:t R=0.98min; [M+H] +=388.95.
Example 44:
5-(3-methoxymethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxymethyl-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 01:t R=0.94min; [M+H] +=421.95.
Example 45:
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-thiazole-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-4-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.01min; [M+H] +=394.81.
Example 46:
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with N, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-pyridine-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 01:t R=0.93min; [M+H] +=388.95.
Example 47:
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-pyridin-4-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.01min; [M+H] +=389.64.
Example 48:
[2-(2-ethanoyl-pyridin-4-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D (step 2), continue with B, from 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-pyridin-4-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-benzyl chloride base-chloro-formic ester begin to prepare.
LC-MS-condition 01:t R=0.97min; [M+H] +=385.93.
Example 49:
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiene-3-yl-methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiene-3-yl-methyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.03min; [M+H] +=394.0.
Example 50:
Between 2-methyl-5--tolyl-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] between triazole-4-base amine and 2-methyl-5--tolyl-thiazole-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.06min; [M+H] +=422.18.
Example 51:
5-phenyl-oxazoles-4-formic acid [2-(3-ethanoyl-isoxazole-5-base methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with L (3 weeks of reaction times), from 2-[3-(2-methyl-[1,3] dioxolane-2-yl)-isoxazole-5-base methyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.01min; [M+H] +=379.2.
Example 52:
5-(3-isopropoxy methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-isopropoxy methyl-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.04min; [M+H 2O+H] +=467.82.
Example 53:
5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.05min; [M+H 2O+H] +=481.98.
Example 54:
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] between triazole-4-base amine and 2-methyl-5--tolyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.99min; [M+H] +=422.13.
Example 55:
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=1.01min; [M+H] +=442.03.
Example 56:
Between 5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] between triazole-4-base amine and 5--tolyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.94min; [M+H] +=408.12.
Example 57:
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.94min; [M+H] +=408.12.
Example 58:
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=1.02min; [M+H] +=476.0.
Example 59:
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluoro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.91min; [M+H] +=412.05.
Example 60:
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.78min; [M+H] +=436.98.
Example 61:
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.96min; [M+H] +=427.95.
Example 62:
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=1.04min; [M+H] +=492.01.
Example 63:
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(4-fluoro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.91min; [M+H] +=412.01.
Example 64:
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.99min; [M+H] +=478.0.
Example 65:
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.9min; [M+H] +=424.07.
Example 66:
5-(3-fluoro-phenyl)-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluoro-phenyl)-thiazole-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.00min; [M+H] +=411.85.
Example 67:
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 01:t R=0.98min; [M+H] +=394.94.
Example 68:
[2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D, continue with B, from 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (2-chloro-phenyl)-methyl alcohol begins to prepare.
LC-MS-condition 01:t R=0.98min; [M+H] +=391.9.
Example 69:
(E)-and N-[2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide:
According to universal program A, continue with B, from 2-[2-(2-methyl-[1,3] dioxolane-2-yl)-thiazole-5-ylmethyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(4-trifluoromethyl-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 01:t R=1.02min; [M+H] +=421.90.
Example 70:
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(114mg, 1.18mmol) processing 5-phenyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides (60mg, 0.16mmol) solution in AcCN (1.6mL), and, pass through diatomite filtration subsequently with reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent and resistates is dissolved among the EA (10mL), with water (10mL) and salt water washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the foamed title compound that is white in color to be provided.
LC-MS-condition 02:t R=0.97min; [M+H] +=379.06.
Example 71:
[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
According to universal program D, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and (2-chloro-phenyl)-methyl alcohol begins to prepare.
LC-MS-condition 01:t R=0.96min; [M+H] +=391.92.
Example 72:
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiophene-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 01:t R=0.99min; [M+H] +=393.92.
Example 73:
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.99min; [M+H] +=394.94.
Example 74:
(E)-and N-[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(4-trifluoromethyl-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 02:t R=1.03min; [M+H] +=421.89.
Example 75:
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] between triazole-4-base amine and 2-methyl-5--tolyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.95min; [M+H] +=423.12.
Example 76:
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.98min; [M+H] +=442.98.
Example 77:
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.90min; [M+H] +=409.04.
Example 78:
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.98min; [M+H] +=477.16.
Example 79:
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluoro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.86min; [M+H] +=413.12.
Example 80:
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.71min; [M+H] +=438.13.
Example 81:
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-chloro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.92min; [M+H] +=429.02.
Example 82:
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=1.00min; [M+H] +=492.95.
Example 83:
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(4-fluoro-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.86min; [M+H] +=413.09.
Example 84:
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.95min; [M+H] +=479.04.
Example 85:
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.85min; [M+H] +=425.02.
Example 86:
(E)-and N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(4-trifluoromethyl-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05:t R=0.88min; [M+H] +=422.04.
Example 87:
(E)-and N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(3-trifluoromethoxy-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05:t R=0.90min; [M+H] +=438.02.
Example 88:
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.90min; [M+H] +=439.04.
Example 89:
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and 5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.92min; [M+H] +=427.00.
Example 90:
Between 2-methyl-5--tolyl-thiazole-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] between triazole-4-base amine and 2-methyl-5--tolyl-thiazole-4-formic acid begins to prepare.
LC-MS-condition 05:t R=0.96min; [M+H] +=438.97.
Example 91:
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-oxazoles-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, from 1-[2-(4-amino-[1,2,3] triazole-2-ylmethyl)-oxazoles-4-yl]-ethyl ketone and 5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=0.94min; [M+H] +=379.22.
Example 92:
2-methoxymethyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-methoxymethyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.00min; [M+H] +=422.0.
Example 93:
2-(2-methoxyl group-ethyl)-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-(2-methoxyl group-ethyl)-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.02min; [M+H] +=436.08.
Example 94:
2-butyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-butyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.13min; [M+H] +=433.99.
Example 95:
2-sec.-propyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-sec.-propyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.10min; [M+H] +=420.42.
Example 96:
(E)-and N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide:
According to universal program A, continue with B, from 2-[4-(2-methyl-[1,3] dioxolane-2-yl)-thiazol-2-yl methyl]-2H-[1,2,3] triazole-4-base amine and (E)-3-(2-trifluoromethyl-phenyl)-vinylformic acid begins to prepare.
LC-MS-condition 05:t R=0.87min; [M+H] +=422.02.
Example 97:
2-benzyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-benzyl-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.11min; [M+H] +=468.06.
Example 98:
3-{4-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-base amine formyl]-5-phenyl-oxazoles-2-yl }-propionic acid uncle-butyl ester:
According to universal program A, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 2-(2-tert-butoxycarbonyl-ethyl)-5-phenyl-oxazoles-4-formic acid begins to prepare.
LC-MS-condition 02:t R=1.12min; [M+H] +=506.00.
Example 99:
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(86mg, 0.89mmol) processing 5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides (49mg, 0.12mmol) solution in AcCN (2.0mL), and, pass through diatomite filtration subsequently with reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent and resistates is dissolved among the EA (10mL), with water (10mL) and salt water washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is the yellow solid shape to be provided.
LC-MS-condition 02:t R=1.03min; [M+H] +=410.85.
Example 100:
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(107mg, 1.11mmol) handle between 2-methyl-5--tolyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides (60mg, 0.15mmol) solution in AcCN (2.0mL), and, pass through diatomite filtration subsequently with reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent and resistates is dissolved among the EA (10mL), with water (10mL) and salt water washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound that is the yellow solid shape to be provided.
LC-MS-condition 02:t R=1.04min; [M+H] +=407.07.
Example 101:
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(91mg, 0.94mmol) processing 5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides (54mg, 0.13mmol) solution in AcCN (1.5mL), and, pass through diatomite filtration subsequently with reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent and resistates is dissolved among the EA (10mL), with water (10mL) and salt water washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound of the solid state that is white in color to be provided.
LC-MS-condition 02:t R=1.06min; [M+H] +=426.75.
Example 102:
Between 5--tolyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(81mg, 0.84mmol) handle between 5--tolyl-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides (44mg, 0.11mmol) solution in AcCN (1.5mL), and, pass through diatomite filtration subsequently with reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent and resistates is dissolved among the EA (10mL), with water (10mL) and salt water washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound of the solid state that is white in color to be provided.
LC-MS-condition 02:t R=1.01min; [M+H] +=392.97.
Example 103:
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(85mg, 0.85mmol) processing 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid 2-[2-(1-hydroxyl-ethyl)-oxazoles-5-ylmethyl]-2H-[1,2,3] triazole-4-yl }-acid amides (54mg, 0.11mmol) solution in AcCN (1.5mL), and, pass through diatomite filtration subsequently with reaction mixture stirred overnight at room temperature.Under reduced pressure remove solvent and resistates is dissolved among the EA (10mL), with water (10mL) and salt water washing.With organic layer through MgSO 4Drying is filtered, and is under reduced pressure removed solvent so that the title compound of the solid state that is white in color to be provided.
LC-MS-condition 02:t R=1.09min; [M+H] +=476.95.
Example 104:
[2-(2-ethanoyl-oxazoles-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester:
Be equipped with magnetic stirring bar in flame-dried round-bottomed flask and at inert atmosphere (N 2) under, at room temperature with MnO 2(13mg, 0.13mmol) handle 2-[2-(1-hydroxyl-ethyl)-oxazoles-4-ylmethyl]-2H-[1,2,3] triazole-4-yl }-carboxylamine 2-chloro-benzyl ester (10mg, 0.03mmol) solution in AcCN (5.0mL), and reaction mixture is stirred 2h down at 50 ℃, pass through diatomite filtration subsequently.
TLC：rf(EA)＝0.60。LC-MS-condition 02:t R=0.97min; [M+H] +=376.04.
Example 105:
5-(6-trifluoromethyl-pyridine-2-yl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides:
According to universal program Z1, continue with B, from 2-[5-(2-methyl-[1,3] dioxolane-2-yl)-furans-2-ylmethyl]-2H-[1,2,3] triazole-4-base amine and 5-(6-trifluoromethyl-pyridine-2-yl)-oxazole-4-formic acid lithium salts begin to prepare.
LC-MS-condition 01:t R=0.91min; [M+H] +=446.99.
II. biological assay
External test
ALX receptor agonist activity according to following determination of experimental method formula (I) compound.
Experimental technique:
Intracellular Ca2+ is measured:
Make the cell of human ALX acceptor of expression recombinant and G Protein G α 16 (HEK293-hALXR-G α 16) in growth medium (GM), grow to 80% degrees of fusion.With cell dissociation damping fluid (Invitrogen, 13151-014) cell is separated from culture dish, and with the at room temperature centrifugal 5min of 1 ' 000rpm, be collected in and measure damping fluid (the AB) (Hunk of equal portions (Hank) BSS (Gibco, 14065-049) with no phenol red DMEM (Gibco, 11880-028)) in.Under 37 ℃ at 5%CO 2Down, be supplemented with 1 μ M Fluo-4 (AM) (TEFLABS.COM, 0152), 0.04% (v/v) Pluronic F-127 (Molecular Probes, P6866) and 20mM HEPES (Gibco, after cultivating 60m0in among AB 15630-056), washed cell and resuspending are in AB.Then, in 384 hole FLIPR assay plate (Greiner, 781091) and with the centrifugal 1min of 1 ' 000rpm, make its sedimentation with 50 ' 000 cell inoculations among every hole 70 μ l.With the stock solution of the DMSO formulations prepared from solutions test compounds of concentration 10mM, and in AB serial dilution to activating the required concentration of dose response curve.Use agonist for referencial use with WKYMVm (Phoenix Peptides).According to the standard specification of manufacturers operation FLIPR384 instrument (Molecular Devices), add 4 μ l and be dissolved in test compound among the 10mM DMSO, and before experiment earlier to measure the damping fluid dilution, obtain the test compounds of required ultimate density.The change in fluorescence of test compounds front and back is added in monitoring under lex=488nm and lem=540nm.After obtaining adding compound behind the deduction baseline, exceed the emission peak of baseline.Behind deduction baseline value (adding AB), proofread and correct numerical value with respect to height control group (WKYMVm compound, 10nM ultimate density).Service routine XLlfit 3.0 (IDBS) is with single-point dose response curve and the calculating EC of data fitting to equation (A+ ((B-A)/(1+ ((C/x) ^D)))) 50Value.
At the ALX acceptor, the agonist activity (EC of all exemplary compounds 50Value) in the scope of 0.03-1850nM, mean value is 60nM.The agonist activity of selected compounds is showed in the table 1.
Table 1
Compound EC 50 [nM]
Example 1:5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 1.8
Example 5:5-phenyl-oxazoles-4-formic acid [2-(5-oxygen-hexyl)-2H-[1,2,3] triazole-4-yl]-acid amides 1.6
Example 8:(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide 1.2
Example 21:5-(3-methoxyl group-4-methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 53
Example 26:2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 2.0
Example 30:2-cyclopropyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 0.8
Example 33:5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 2.8
Example 35:[2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester 8.5
Example 36:5-phenyl-oxazole-4-formic acid [2-(5,5-two fluoro-hexyls)-2H-[1,2,3] triazole-4-yl]-acid amides 4.9
Example 37:5-phenyl-oxazoles-4-formic acid [2-(5-methane sulfonyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 24
Example 38:5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 1.9
Example 40:[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester 1.3
Example 41:[2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester 21
Example 42:5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 2.1
Example 43:5-phenyl-oxazoles-4-formic acid [2-(6-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 203
Example 49:5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiene-3-yl-methyl)-2H-[1,2,3] triazole-4-yl]-acid amides 57
Between example 50:2-methyl-5--tolyl-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 98
Example 71:[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester 23
Example 91:5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-oxazoles-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 0.7
Example 93:2-(2-methoxyl group-ethyl)-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 5.2
Example 99:5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 8.1
Example 104:[2-(2-ethanoyl-oxazoles-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester 1.4
Example 105:5-(6-trifluoromethyl-pyridine-2-yl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides 36

Claims (17)

1. the compound of a formula (I):
Figure FPA00001161879100011
Wherein:
A represents phenyl or heterocyclic radical, and wherein two substituting groups are 1, and 3-arranges;
Or A represents propane-1,3-two bases;
E represents *-(C 1-C 4) alkyl-O-,-CH=CH-or
Figure FPA00001161879100012
Wherein asterisk is indicated and R 1The key of binding;
Q represents O or S;
R 3Expression hydrogen, (C 1-C 4) alkyl, cyclopropyl, (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl, benzyl or-CH 2CH 2C (O) OtBu;
R 1Expression pyridyl or aryl, this group be unsubstituted, through single replacement, replace or through three replacements, wherein substituting group is independently selected from: halogen, (C through two 1-C 4) alkyl, (C 1-C 4) alkoxyl group, (C 1-C 4) fluoroalkyl, (C 1-C 4) Fluoroalkyloxy, two-[(C 1-C 3) alkyl]-amino and (C 1-C 4) alkoxyl group-(C 1-C 2) alkyl; And
R 2Expression-CO-(C 1-C 3) alkyl ,-CF 2-(C 1-C 3) alkyl or-SO 2-(C 1-C 3) alkyl;
Or the salt of this compounds.
2. the compound of formula as claimed in claim 1 (I), wherein:
A represents phenyl-1,3-two bases, furans-2,5-two Ji, oxazoles-2,4-two Ji, oxazoles-2,5-two bases, thiophene-2,4-two bases, thiophene-2,5-two bases, thiazole-2,4-two bases, thiazole-2,5-two bases, pyridine-2,4-two bases, pyridine-2,6-two bases or propane-1,3-two bases;
Or the salt of this compounds.
3. as the compound of each formula (I) in claim 1 or 2, wherein:
A represents furans-2,5-two bases, R 2Be connected 2 Wei De oxazoles-2,4-two bases, R 2Be connected 4 Wei De oxazoles-2,4-two bases, R 2Be connected 2 Wei De oxazoles-2,5-two bases, thiophene-2,5-two bases or R 2Be connected 4 thiazole-2,4-two bases;
Or the salt of this compounds.
4. as the compound of each formula (I) in the claim 1 to 3, wherein:
A represents furans-2,5-two bases or thiophene-2,5-two bases;
Or the salt of this compounds.
5. as the compound of each formula (I) in claim 1 or 2, wherein:
A represents propane-1,3-two bases;
Or the salt of this compounds.
6. as the compound of each formula (I) in the claim 1 to 5, wherein:
E represents *-(C 1-C 4) alkyl-O-or-CH=CH-;
Wherein asterisk is indicated and R 1The key of binding;
Or the salt of this compounds.
7. as the compound of each formula (I) in the claim 1 to 5, wherein E represents:
Figure FPA00001161879100031
Wherein asterisk is indicated and R 1The key of binding;
Or the salt of this compounds.
8. as the compound of each formula (I) in claim 1 to 5 or 7, wherein:
R 3Expression hydrogen or methyl;
Or the salt of this compounds.
9. as the compound of each formula (I) in the claim 1 to 8, wherein:
R 1The expression phenyl, it is unsubstituted, replace or through two replacements, wherein substituting group is independently selected from: halogen, (C through single 1-C 4) alkyl, (C 1-C 4) alkoxyl group, trifluoromethyl, trifluoromethoxy and dimethylamino;
Or the salt of this compounds.
10. as the compound of each formula (I) in the claim 1 to 9, wherein:
R 2Expression-CO-(C 1-C 3) alkyl;
Or the salt of this compounds.
11. the compound of formula as claimed in claim 1 (I), it is selected from:
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides; And
[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
Or the salt of this compounds.
12. the compound of formula as claimed in claim 1 (I), it is selected from:
5-phenyl-oxazoles-4-formic acid [2-(5-oxygen-hexyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-chloro-phenyl)-acrylamide;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-neighbour-tolyl-acrylamide;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(2-chloro-4-fluoro-phenyl)-acrylamide;
(E)-N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-between-tolyl-acrylamide;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-is right-tolyl-acrylamide;
(E)-and N-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-methoxyl group-phenyl)-acrylamide;
5-(3,5-dimethyl-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-4-methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-neighbour-tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-ethyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-cyclopropyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(3-ethanoyl-benzyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-phenyl-oxazole-4-formic acid [2-(5,5-two fluoro-hexyls)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(5-methane sulfonyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
[2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-[3-(2-methoxyl group-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(6-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxymethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-thiazole-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-pyridine-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-pyridin-4-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(2-ethanoyl-pyridin-4-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiene-3-yl-methyl)-2H-[1,2,3] triazole-4-yl]-acid amides; And
Between 2-methyl-5--tolyl-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Or the salt of this compounds.
13. the compound of formula as claimed in claim 1 (I), it is selected from:
5-phenyl-oxazoles-4-formic acid [2-(3-ethanoyl-isoxazole-5-base methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-isopropoxy methyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-[3-(2-isopropoxy-ethyl)-phenyl]-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 5--tolyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(5-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-thiazole-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
(E)-and N-[2-(2-ethanoyl-thiazole-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
5-phenyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiophene-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
(E)-and N-[2-(5-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethyl-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-dimethylamino-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(4-fluoro-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-methoxyl group-phenyl)-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
(E)-and N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(4-trifluoromethyl-phenyl)-acrylamide;
(E)-and N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(3-trifluoromethoxy-phenyl)-acrylamide;
5-(3-methoxyl group-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-thiazole-4-formic acid [2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-phenyl-oxazoles-4-formic acid [2-(4-ethanoyl-oxazoles-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methoxymethyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-(2-methoxyl group-ethyl)-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-butyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-sec.-propyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
(E)-and N-[2-(4-ethanoyl-thiazol-2-yl methyl)-2H-[1,2,3] triazole-4-yl]-3-(2-trifluoromethyl-phenyl)-acrylamide;
2-benzyl-5-phenyl-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
3-{4-[2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-base amine formyl]-5-phenyl-oxazoles-2-yl }-the propionic acid tert-butyl ester;
5-(3-fluoro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 2-methyl-5--tolyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
5-(3-chloro-phenyl)-2-methyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
Between 5--tolyl-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazoles-4-formic acid [2-(2-ethanoyl-oxazoles-5-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides;
[2-(2-ethanoyl-oxazoles-4-ylmethyl)-2H-[1,2,3] triazole-4-yl]-carboxylamine 2-chloro-benzyl ester; And
5-(6-trifluoromethyl-pyridine-2-yl)-oxazoles-4-formic acid [2-(5-ethanoyl-furans-2-ylmethyl)-2H-[1,2,3] triazole-4-yl]-acid amides; Or the salt of this compounds.
14. the compound of formula as claimed in claim 1 (I) or its pharmacy acceptable salt, it is as medicament.
15. a pharmaceutical composition, it contains as inert excipients in the compound of the formula as claimed in claim 1 (I) of activeconstituents or its pharmacy acceptable salt and at least a treatment.
16. the compound of a formula as claimed in claim 1 (I) or the purposes of its pharmacy acceptable salt, it is used to make in order to prevention or treatment and is selected from following disease and in order to regulate the medicament of immunne response: the disease of the retroviral infection of inflammatory disease, obstructive airway disease, supersensitivity symptom, HIV mediation, cardiovascular disorder, neural inflammation, nervous disorders, pain, Protein virus mediation and the illness of kind of starch mediation.
17. the compound of formula as claimed in claim 1 (I) or its pharmacy acceptable salt, it is used to prevent or treat to be selected from following disease: the disease of the retroviral infection of inflammatory disease, obstructive airway disease, supersensitivity symptom, HIV mediation, cardiovascular disorder, neural inflammation, nervous disorders, pain, Protein virus mediation and the illness of kind of starch mediation; And be used to regulate immunne response.
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